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Objectives: To investigate differences in surgical time, the distance the surgical instrument travelled and number of movements required to complete manual phacoemulsification cataract surgery versus femtosecond laser cataract surgery., Design: Non-randomised comparative case series., Setting: Single surgery site, Moorfields Eye Hospital, UK., Participants: 40 cataract surgeries of 40 patients., Interventions: Laser-assisted and manual phacoemulsification cataract surgery. Laser-assisted surgery cases were performed using the AMO Catalys platform., Primary and Secondary Outcome Measures: Computer vision tracking software PhacoTracking were applied to the recordings to establish the distance the instrument travelled, total number of movements (the number of times an instrument stops and starts moving) and time taken for surgery steps including phacoemulsification, irrigation-aspiration (IA) and overall surgery time. The time taken for laser docking and delivery was not included in the analyses., Results: Data on 19 laser-assisted and 19 manual phacoemulsification surgeries were analysed (two cases were excluded due to insufficient video-recording quality). There were no differences in the number of instrument moves, the distance the instrument travelled or time taken to complete the phacoemulsification stage. However for IA, the number of instrument moves (manual: mean 20 (SD 15) vs laser: mean 38 (SD 22), P=0.008) and time taken (manual: mean 75 s (SD 24) vs laser: mean 108 s (SD 36), P=0.003) were significantly greater for laser cases. For laser versus manual cases overall, there was no difference in number of moves or the distance the instrument travelled, but laser cases took longer (mean 88 s, P=0.049)., Conclusions: Laser cataract surgery cases took longer to complete without accounting for the time taken to complete the laser procedure itself. This appears to be in part due to IA requiring more instrument manoeuvres and taking longer to complete. Data from a large randomised series would better elucidate this relationship., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Anastasis (Greek for "rising to life") is a recently discovered cell recovery phenomenon whereby dying cells can reverse late-stage cell death processes that are generally assumed to be intrinsically irreversible. Promoting anastasis could in principle rescue or preserve injured cells that are difficult to replace such as cardiomyocytes or neurons, thereby facilitating tissue recovery. Conversely, suppressing anastasis in cancer cells, undergoing apoptosis after anti-cancer therapies, may ensure cancer cell death and reduce the chances of recurrence. However, these studies have been hampered by the lack of tools for tracking the fate of cells that undergo anastasis in live animals. The challenge is to identify the cells that have reversed the cell death process despite their morphologically normal appearance after recovery. To overcome this difficulty, we have developed Drosophila and mammalian CaspaseTracker biosensor systems that can identify and permanently track the anastatic cells in vitro or in vivo. Here, we present in vivo protocols for the generation and use of the CaspaseTracker dual biosensor system to detect and track anastasis in Drosophila melanogaster after transient exposure to cell death stimuli. While conventional biosensors and protocols can label cells actively undergoing apoptotic cell death, the CaspaseTracker biosensor can permanently label cells that have recovered after caspase activation - a hallmark of late-stage apoptosis, and simultaneously identify active apoptotic processes. This biosensor can also track the recovery of the cells that attempted other forms of cell death that directly or indirectly involved caspase activity. Therefore, this protocol enables us to continuously track the fate of these cells and their progeny, facilitating future studies of the biological functions, molecular mechanisms, physiological and pathological consequences, and therapeutic implications of anastasis. We also discuss the appropriate controls to distinguish cells that undergo anastasis from those that display non-apoptotic caspase activity in vivo.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell-mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR)., Objectives: We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP., Methods: We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR -/- ) mast cells. The role of ox-CaMKII in mast cell activation was further investigated., Results: Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca 2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR -/- mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation., Conclusions: These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens., Objective: We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p., Methods: We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1 -/- mice. The role of miR-511-3p in macrophage polarization and cockroach allergen-induced lung inflammation in mice transfected with adeno-associated virus (AAV)-miR-511-3p (AAV-cytomegalovirus-miR-511-3p-enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed., Results: Mrc1 -/- lung macrophages showed a significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1 -/- mice had an exacerbated lung inflammation with increased levels of cockroach allergen-specific IgE and T H 2/T H 17 cytokines in a cockroach allergen-induced mouse model compared with WT mice. Macrophages from Mrc1 -/- mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV-miR-511-3p showed a significant reduction in cockroach allergen-induced inflammation. Profiling of macrophages with or without miR-511-3p overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D 2 synthase (Ptgds) and its product PGD 2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511-3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects., Conclusion: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Two-dimensional (2D) materials are drawing growing attention for next-generation electronics and optoelectronics owing to its atomic thickness and unique physical properties. One of the challenges posed by 2D materials is the large source/drain (S/D) series resistance due to their thinness, which may be resolved by thickening the source and drain regions. Recently explored lateral graphene-MoS 2 1-3 and graphene-WS 2 1,4 heterostructures shed light on resolving the mentioned issues owing to their superior ohmic contact behaviors. However, recently reported field-effect transistors (FETs) based on graphene-TMD heterostructures have only shown n-type characteristics. The lack of p-type transistor limits their applications in complementary metal-oxide semiconductor electronics. In this work, we demonstrate p-type FETs based on graphene-WSe 2 lateral heterojunctions grown with the scalable CVD technique. Few-layer WSe 2 is overlapped with the multilayer graphene (MLG) at MLG-WSe 2 junctions such that the contact resistance is reduced. Importantly, the few-layer WSe 2 only forms at the junction region while the channel is still maintained as a WSe 2 monolayer for transistor operation. Furthermore, by imposing doping to graphene S/D, 2 orders of magnitude enhancement in I on /I off ratio to ∼10 8 and the unipolar p-type characteristics are obtained regardless of the work function of the metal in ambient air condition. The MLG is proposed to serve as a 2D version of emerging raised source/drain approach in electronics.

Two-dimensional (2D) transition-metal dichalcogenide (TMDC) semiconductors are important for next-generation electronics and optoelectronics. Given the difficulty in growing large single crystals of 2D TMDC materials, understanding the factors affecting the seed formation and orientation becomes an important issue for controlling the growth. Here, we systematically study the growth of molybdenum disulfide (MoS 2 ) monolayer on c-plane sapphire with chemical vapor deposition to discover the factors controlling their orientation. We show that the concentration of precursors, that is, the ratio between sulfur and molybdenum oxide (MoO 3 ), plays a key role in the size and orientation of seeds, subsequently controlling the orientation of MoS 2 monolayers. High S/MoO 3 ratio is needed in the early stage of growth to form small seeds that can align easily to the substrate lattice structures, while the ratio should be decreased to enlarge the size of the monolayer at the next stage of the lateral growth. Moreover, we show that the seeds are actually crystalline MoS 2 layers as revealed by high-resolution transmission electron microscopy. There exist two preferred orientations (0° or 60°) registered on sapphire, confirmed by our density functional theory simulation. This report offers a facile technique to grow highly aligned 2D TMDCs and contributes to knowledge advancement in growth mechanism.

Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A + TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1 + ) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10 high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10 high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1 + myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1 + myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1 + myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic niche formation and metastasis, and may serve as a potential therapeutic target in human cancer.

Objective: To analyze timeline of antiretroviral therapy (ART) initiation among newly diagnosed HIV/AIDS from 2010 to 2014, as well as influencing factors. Methods: Data from the Chinese HIV/AIDS Comprehensive Response Information Management System was used to collect newly diagnosed HIV/AIDS cases from January 1, 2010 to December 31, 2014. Inclusion criteria of HIV/AIDS were confirmed cases and clinically diagnosed HIV positive, Chinese mainland cases, 14 years old and above, the first CD4(+)T lymphocyte ≤350 cells/μl in the follow up period. A total of 177 971 HIV/AIDS cases were included in this study. The general demographic characteristics (gender, age, ethnicity, education, occupation, etc.), infection routes, sample sources, CD4(+)T lymphocyte level and other information were collected from the database. Chi square test was used to analyze univariate factor of the timeliness of ART initiation. Multivariate logistic regressions were used to analyze potential factors associated with timeliness of ART initiation. Results: Out of the 17 7971 cases, 130 679 (73.4%) were males. The proportion of the timeliness of ART initiation was 55% (97 915). The proportion of timeline of ART within 15 d increased from 26.4% (4 319/16 388) in 2010 to 39.7% (20 212/50 889) in 2014. The highest proportion was in the group of patients infected by illegal blood (plasma) donation, which was 38% (945). The proportion of timeline of ART within 30 d increased from 43.2% (7 077/16 388) in 2010 to 63% (32 070/50 889) in 2014.The highest proportion was in the group of patients infected by heterosexual transmission, which was 58.3% (73 098). Multivariate logistic regression analysis on timeliness of ART showed that the factors of timeliness of ART initiation of HIV/AIDS as follow. The possibility of timeliness of ART among patients who were female, education of junior high school and above, ethnic group of Han, farmers, married were higher, with OR values at 1.08, 1.09, 1.13, 1.05 and 1.12. The possibilities of timeliness of ART in group of patients aging 25-34, 35-44, 45-54 and ≥55 years old were higher than that of the group of patients aging 15-24 years old, with OR values at 1.13, 1.31, 1.46 and 1.51, respectively. The possibilities of timeliness of ART among the homosexuals, injection drug use and sexual contact plus injection drug use cases were lower than that of the heterosexuals, with OR values at 0.86, 0.59 and 0.72, respectively. The possibilities of timeliness of ART among patients whose HIV diagnosis from hospitals and detention centers were lower than that of patients whose HIV diagnosis from volunteer testing and counseling, with OR values at separately 0.90 and 0.29. The possibilities of timeliness of ART among patients whose CD4(+)T lymphocyte at 50-99, 100-199, 200-350 cells/μl were lower than that of the patients whose CD4(+)T lymphocyte count at 0-49 cells/μl, with OR values at 0.84, 0.64 and 0.40, respectively. All the P values above was<0.05. Conclusion: The proportion of timeliness of ART increased annually from 2010 to 2014. Those who were men, unmarried or divorced, at younger age, injection drug use, diagnosis from hospitals and detention centers and high CD4(+)T lymphocyte levels were related to the timeliness of ART.

Objective: To analyze the status of marriage and HIV transmission between couples in newly reported HIV cases before diagnoses were made, among men who have sex with men (MSM) in China. Methods: Baseline and follow-up information related to newly reported cases in 2014 were collected from the Chinese HIV/AIDS Comprehensive Response Information Management System. Infected MSM who were older than 22 years of age were included in this study. HIV cases were divided into sero-concordant or sero-discordant group, according to the HIV status of the couple who were tested 180 days post-diagnosis. Multivariate logistic regression method was used to analyze the potential factors associated with HIV transmission between couples before diagnosis was made. Results: A total of 5 081 (22.7 % ) of the HIV infected MSM who had couples, were included in this study. A total of 3 715 cases had their couples tested 180 days after the diagnosis was made. 7.6 % (282) had positive couples. Results from the multivariate logistic regression analysis showed that factors as: older than 60 ( OR =2.64, 95 % CI : 1.50-4.65) years of age, being minorities ( OR =1.93, 95 % CI : 1.13-3.29), having CD(4)(+)T cells less than 500 cells/μl (<200: OR =2.91, 95 %CI : 1.82-4.65; 200-349: OR =1.98, 95 %CI : 1.22-3.23; 350-500: OR =1.69, 95 %CI : 1.00-2.86), with self-reported unsafe behaviors ( OR =1.92, 95 % CI : 1.44-2.58) etc. , were more likely to transmit HIV to their couples before the diagnosis was made. Conclusion: Behavior interventions and early HIV testing should be promoted, especially among those MSM who had couples, to avoid inter-spousal transmission.

Voltage-gated sodium channel α-subunit type I (Na V 1.1, encoded by SCN1A gene) plays a critical role in the excitability of brain. Downregulation of SCN1A expression is associated with epilepsy, a common neurological disorder characterized by recurrent seizures. Here we reveal a novel role of malate dehydrogenase 2 (MDH2) in the posttranscriptional regulation of SCN1A expression under seizure condition. We identified that MDH2 was an RNA binding protein that could bind two of the four conserved regions in the 3' UTRs of SCN1A. We further showed that knockdown of MDH2 or inactivation of MDH2 activity in HEK-293 cells increased the reporter gene expression through the 3' UTR of SCN1A, and MDH2 overexpression decreased gene expression by affecting mRNA stability. In the hippocampus of seizure mice, the upregulation of MDH2 expression contributed to the decrease of the Na V 1.1 levels at posttranscriptional level. In addition, we showed that the H 2 O 2 levels increased in the hippocampus of the seizure mice, and H 2 O 2 could promote the binding of MDH2 to the binding sites of Scn1a gene, whereas β-mercaptoethanol decreased the binding capability, indicating an important effect of the seizure-induced oxidation on the MDH2-mediated downregulation of Scn1a expression. Taken together, these data suggest that MDH2, functioning as an RNA-binding protein, is involved in the posttranscriptional downregulation of SCN1A expression under seizure condition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Neonatal maternal separation (MS) is a major early life stress that increases the risk of emotional disorders, visceral pain perception and other brain dysfunction. Elevation of toll-like receptor 4 (TLR4) signaling in the paraventricular nucleus (PVN) precipitates early life colorectal distension (CRD)-induced visceral hypersensitivity and pain in adulthood. The present study aimed to investigate the role of TLR4 signaling in the pathogenesis of postnatal MS-induced visceral hypersensitivity and pain during adulthood. The TLR4 gene was selectively knocked out in C57BL/10ScSn mice ( Tlr4 -/- ). MS was developed by housing the offspring alone for 6 h daily from postnatal day 2 to day 15. Visceral hypersensitivity and pain were assessed in adulthood. Tlr4 +/+ , but not Tlr4 -/- , mice that had experienced neonatal MS showed chronic visceral hypersensitivity and pain. TLR4 immunoreactivity was observed predominately in microglia in the PVN, and MS was associated with an increase in the expression of protein and/or mRNA levels of TLR4, corticotropin-releasing factor (CRF), CRF receptor 1 (CRFR1), tumor necrosis factor-α, and interleukin-1β in Tlr4 +/+ mice. These alterations were not observed in Tlr4 -/- mice. Local administration of lipopolysaccharide, a TLR4 agonist, into the lateral cerebral ventricle elicited visceral hypersensitivity and TLR4 mRNA expression in the PVN, which could be prevented by NBI-35965, an antagonist to CRFR1. The present results indicate that neonatal MS induces a sensitization and upregulation of microglial TLR4 signaling activity, which facilitates the neighboring CRF neuronal activity and, eventually, precipitates visceral hypersensitivity in adulthood. Highlights (1)Neonatal MS does not induce chronic visceral hypersensitivity and pain in Tlr4 -/- mice.(2)Neonatal MS increases the expression of TLR4 mRNA, CRF protein and mRNA, CRFR1 protein, TNF-α protein, and IL-1β protein in Tlr4 +/+ mice.(3)TLR4 agonist LPS (i.c.v.) elicits visceral hypersensitivity and TLR4 mRNA expression in the PVN.

Cell growth experiments with a microfluidic device produce large-scale time-lapse image data, which contain important information on cell growth and patterns in their genealogy. To extract such information, we propose a scheme to segment and track bacterial cells automatically. In contrast with most published approaches, which often split segmentation and tracking into two independent procedures, we focus on designing an algorithm that describes cell properties evolving between consecutive frames by feeding segmentation and tracking results from one frame to the next one. The cell boundaries are extracted by minimizing the distance regularized level set evolution (DRLSE) model. Each individual cell was identified and tracked by identifying cell septum and membrane as well as developing a trajectory energy minimization function along time-lapse series. Experiments show that by applying this scheme, cell growth and division can be measured automatically. The results show the efficiency of the approach when testing on different datasets while comparing with other existing algorithms. The proposed approach demonstrates great potential for large-scale bacterial cell growth analysis., Competing Interests: We declare we have no competing interests.

Objective: To analyze the survival time of newly diagnosed HIV/AIDS cases and related factors in China in 2010. Methods: The reporting cards and follow-up cards of HIV/AIDS cases reported as of 31 December 2015 were collected from national AIDS information system. The newly diagnosed HIV/AIDS cases in 2010 were selected. The information of follow-up intervention, CD(4+)T cells (CD(4)) testing, antiretroviral treatment and mortality of the cases from 2010 to 2015 were analyzed. Life table method was applied to calculate the survival probability. Kaplan-Meier was used to draw survival curve and Cox proportion hazard regression model were used to identify the factors related to survival time. Results: Of the 40 335 HIV/AIDS cases, 11 975(29.7 % ) died of AIDS related diseases. The median survival time was 63.1 months (95 %CI : 63.0-63.2), and the survival rates in 1 year and 5 years were 81.2 % and 69.9 % . Multivariate Cox regression analysis showed that the risk factors for death in the HIV/AIDS cases were age (25-34 years old vs. 15-24 years old: HR =1.41, 95 %CI : 1.29-1.54; 35-34 years old vs. 15-24 years old: HR =1.90, 95 %CI : 1.74-2.07; 45-54 years old vs. 15-24 years old: HR =2.24, 95 %CI : 2.04-2.46; ≥55 years old vs. 15-24 years old: HR =2.81, 95 %CI : 2.57-3.08). The protective factors for death in the HIV/AIDS cases were level of baseline CD(4) counts (CD(4)≥500 cells/μl vs. CD(4)<200 cells/μl: HR =0.12, 95 %CI : 0.11-0.13), receiving antiretroviral therapy (ART vs. no ART: HR =0.11,95 %CI : 0.10-0.12). Conclusion: Survival time of HIV/AIDS cases might be influenced by age, baseline CD(4) count and access to antiretroviral therapy. The early diagnosed and early antiretroviral therapy could extend the survival time of HIV/AIDS cases.

Goal: Reliable recognition of microaneurysms (MAs) is an essential task when developing an automated analysis system for diabetic retinopathy (DR) detection. In this study, we propose an integrated approach for automated MA detection with high accuracy., Methods: Candidate objects are first located by applying a dark object filtering process. Their cross-section profiles along multiple directions are processed through singular spectrum analysis. The correlation coefficient between each processed profile and a typical MA profile is measured and used as a scale factor to adjust the shape of the candidate profile. This is to increase the difference in their profiles between true MAs and other non-MA candidates. A set of statistical features of those profiles is then extracted for a K-nearest neighbor classifier., Results: Experiments show that by applying this process, MAs can be separated well from the retinal background, the most common interfering objects and artifacts., Conclusion: The results have demonstrated the robustness of the approach when testing on large scale datasets with clinically acceptable sensitivity and specificity., Significance: The approach proposed in the evaluated system has great potential when used in an automated DR screening tool or for large scale eye epidemiology studies.

Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of Scn3a expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate Scn3a expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in Scn3a promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased Scn3a expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Na v 1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of Scn3a and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of Scn3a expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.

Influenza H7N9 virus infection causes an acute, highly contagious respiratory illness that triggers cell death of infected cells and airway epithelial destruction. RIP3 is a key regulator of cell death responses to a growing number of viral and microbial agents. This study aimed to investigate the role of RIP3 in inflammation of influenza H7N9 virus infection. Here, RIP3 knock out (RIP3-/-) mice and littermate wild type mice were infected intranasally with influenza H7N9 virus (A/Fujian/S03/2015) to determine the contribution of RIP3 to the inflammatory response of influenza H7N9 virus infection. It was found that RIP3-/- mice infected with H7N9 virus showed higher survival and less weight loss, compared with wild type littermate mice. In addition, RIP3-/- mice had fewer regions of edema, infiltration with inflammatory cells, and alvelolar collapses, and the secretions of IL-1β, IL-6, RANTES and MIP-1 in BALF were significantly decreased on days 3 and 7 p.i. when compared with WT mice. Moreover, caspase 1/IL1β signaling was found to be invovled in RIP3 associated imflammation of influenza H7N9 virus, but not RIP3/MLKL dependent necrosis. In the conclusion, our results indicated that RIP3 deficiency can protect mice from the infection of influenza H7N9 virus by downregulating caspase 1/IL1β signaling, which provided edivence of the RIP3 invovled necroptosis independent manner.

Ulcerative colitis (UC) is a chronic intestinal inflammatory disease. The receptor-interacting protein kinase 3 (RIP3) was reported to be involved in many inflammatory disease. However, the mechanism of RIP3 in the pathogenesis of UC is still unclear. To investigate the effects and possible mechanism of RIP3 in UC pathogenesis, RIP3-/- mice was used in dextran sulfate sodium (DSS)-induced colitis model. It was found that by DSS-induced colitis, RIP3-/- mice showed significantly enhanced colitis symptoms, including increased weight loss, colon shortening, and colonic mucosa damage and severity, but decreased production of interleukin 6 and interleukin 1β. The results showed that RIP3 deficiency could not ameliorate but exacerbate the severity of colitis. On the mechanism, it was found that messenger RNA expressions of several repair-associated cytokines including interleukin 6, interleukin 22, cyclooxygenase 2, epithelial growth factor receptor ligand Epiregulin and matrix metalloproteinase 10 were siginificant decreased in RIP3-/- mice. Thus, RIP3-/- mice exhibited an impaired tissue repair in response to DSS. In a conclusion, RIP3 deficiency exerted detrimental effects in DSS induced colitis partially because of the impaired repair-associated cytokines expression., (Copyright © 2017 John Wiley & Sons, Ltd.)

Genes that are indispensable for survival are essential genes. Many features have been proposed for computational prediction of essential genes. In this paper, the least absolute shrinkage and selection operator method was used to screen key sequence-based features related to gene essentiality. To assess the effects, the selected features were used to predict the essential genes from 31 bacterial species based on a support vector machine classifier. For all 31 bacterial objects (21 Gram-negative objects and ten Gram-positive objects), the features in the three datasets were reduced from 57, 59, and 58, to 40, 37, and 38, respectively, without loss of prediction accuracy. Results showed that some features were redundant for gene essentiality, so could be eliminated from future analyses. The selected features contained more complex (or key) biological information for gene essentiality, and could be of use in related research projects, such as gene prediction, synthetic biology, and drug design.

The lymphocyte-to-monocyte ratio (LMR), as a surrogate marker of systemic inflammation, has been found to be a novel prognostic indicator in various malignancies. Data from 672 advanced epithelial ovarian cancer (EOC) patients treated with neoadjuvant chemotherapy (NAC) followed by debulking surgery were analyzed, and the prognostic value of LMR were evaluated. The optimal cutoff point of LMR in prediction of survival was defined as 3.45 through receiver operating characteristics curve analysis. Patients with low LMR (≤3.45) at diagnosis tended to have more adverse clinical features, such as higher histological grade, chemotherapy resistance, and residual tumor >1cm after debulking surgery. No significant correlation was found between LMR level and age and histological type. Moreover, after NAC, the complete remission (CR) rate for the low-LMR group was lower than those for the high-LMR group (P<0.05). Patients with low LMR had poorer progression-free survival (PFS; P<0.001) and overall survival (OS; P<0.001). Multivariate analysis revealed that low LMR was an independent adverse predictor for PFS and OS. Results indicated that low LMR at diagnosis is a novel independent prognostic factor for advanced EOC. However, prospective study is needed to validate this prognostic factor and biological studies should further investigate the mechanisms underlying the correlation between low LMR and poor prognosis in advanced EOC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objective: To analyze the factors associated with divorce or separation when one of the spouse diagnosed and newly reported as HIV positive, in China. Methods: Data from the Chinese HIV/AIDS Comprehensive Response Information Management System, by December 31, 2015 were used for collection on newly reported HIV cases regarding their baseline information in 2014 and follow-up within one year, among couples and above 18 year olds. HIV cases were divided into divorce/separation group and married group according to their marriage dynamics in one year after being diagnosed as HIV positive. Multivariate logistic regressions were used to analyze potential factors associated with divorce or separation after the diagnoses made. Results: A total of 31 708 HIV cases were included in this study. 22.5% (7 134/31 708) of them got divorced or separated in one year after diagnose being made. 81.6% (25 864/31 708) of them had couples tested in one year after diagnose made and 10.0% (2 599/25 864) of them got divorced or separated. Among 18.4% (5 844/31 708) of the HIV cases who did not have their couples tested in one year after the diagnoses, 77.6% (4 535/5 844) got divorced or separated. For those who did not have their couples tested in one year after the diagnose. Data from the multivariate logistic regression analysis showed that factors as those who were older than 45 (46-60 yr.: OR =1.28, 95 %CI : 1.03-1.58; ≥61 yr.: OR =1.83, 95 %CI : 1.41-2.37), with Han ethnicity ( OR =1.56, 95 %CI : 1.34-1.83), with high school education or above ( OR =1.55, 95 %CI : 1.27-1.90), non-farmers or non-rural laborers ( OR =1.34, 95 %CI : 1.17-1.54), infected through injecting drug use ( OR =1.33, 95 % CI : 1.03-1.71), men who had sex with men ( OR =1.49, 95 % CI : 1.20-1.86), or with childless ( OR =2.35, 95 %CI : 1.78-3.09) etc . were more likely to be divorced or separated after the diagnoses being made, among those who had their couples tested in one year after the diagnoses. Results from the multivariate logistic regression analysis showed that factors as those who were above 60 year olds ( OR =1.32, 95 %CI : 1.12-1.56), with Han ethnicity ( OR =1.27, 95 %CI : 1.13-1.44), with high school education or above ( OR =1.26, 95 %CI : 1.11-1.43), non-farmers or non-rural labors ( OR =1.37, 95 %CI : 1.25-1.51), infected through having sex with men ( OR =1.38, 95 %CI : 1.25-1.54), or without a child ( OR =1.48, 95 % CI : 1.27-1.71), were more likely to be divorced or separated after the diagnoses. Conclusion: A certain proportion of HIV cases got divorced or separated in one year after the diagnosis was made. The proportions of divorce or separation were different among populations. Interventions targeting reducing divorce or separation in certain populations should be integrated into routine care system to reduce the HIV transmission.

Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and Scn3a expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3' UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3' UTR and SCN3A 3' UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3' UTR, which lead to downregulation of Scn1a and upregulation of Scn3a. Furthermore, administration of KD generates β-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and Scn3a by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Anastasis (Greek for "rising to life") is a cell recovery phenomenon that rescues dying cells from the brink of cell death. We recently discovered anastasis to occur after the execution-stage of apoptosis in vitro and in vivo . Promoting anastasis could in principle preserve injured cells that are difficult to replace, such as cardiomyocytes and neurons. Conversely, arresting anastasis in dying cancer cells after cancer therapies could improve treatment efficacy. To develop new therapies that promote or inhibit anastasis, it is essential to identify the key regulators and mediators of anastasis - the therapeutic targets. Therefore, we performed time-course microarray analysis to explore the molecular mechanisms of anastasis during reversal of ethanol-induced apoptosis in mouse primary liver cells. We found striking changes in transcription of genes involved in multiple pathways, including early activation of pro-cell survival, anti-oxidation, cell cycle arrest, histone modification, DNA-damage and stress-inducible responses, and at delayed times, angiogenesis and cell migration. Validation with RT-PCR confirmed similar changes in the human liver cancer cell line, HepG2, during anastasis. Here, we present the time-course whole-genome gene expression dataset revealing gene expression profiles during the reversal of apoptosis. This dataset provides important insights into the physiological, pathological, and therapeutic implications of anastasis., Competing Interests: Competing interests: No competing interests were disclosed.

Objective: To analyze the effects of a follow-up program among newly diagnosed HIV/AIDS cases in 2010 in China. Methods: Database was downloaded on January, 2016 from both HIV/AIDS Case Reporting and Follow-up Cards. Information related to newly diagnosed HIV/AIDS cases in 2010 was extracted from the database. Information on follow-up intervention programs, CD 4 testing, antiretroviral treatment, sexual behavior and mortality from 2010 to 2015 were analyzed. Results: Of the newly diagnosed HIV/AIDS cases in 2010, 70.4% were men and 72.0% with Han ethnicity. Heterosexual transmission accounted for 65.8%. The proportion of having received standardized follow-up increased significantly, with an annually upward trend (trend χ 2 =3 749.77, P <0.01). The proportions of sexual risk behaviors decreased significantly, with safe sexual behaviors over 90%, and having yearly upward trend (trend χ 2 =16 971.98, P <0.01). Among those eligible for antiretroviral therapy, the proportion of initiation the therapy increased from 56.5% in 2010 to 83.2% in 2015, with significant upward trend, annually (trend χ 2 =2 504.86, P <0.01). Over the same period, the proportion of deaths decreased from 12.4% in 2010 to 2.4% in 2015, with significant annual downward trend (trend χ 2 =4 935.89, P <0.01). Conclusion: The standardized follow-up intervention program included the contents of: CD 4 testing; counseling and timely referrals to receive antiretroviral therapy etc. , which were correlated to the reduction on both high risk sexual behaviors and deaths.

Aim: To evaluate the comparative effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on risk of bone fracture in patients with type 2 diabetes mellitus (T2DM)., Methods: PubMed, EMBASE, CENTRAL and ClinicalTrials.gov were systematically searched from inception to 27 January 2016 to identify randomized controlled trials (RCTs) reporting the outcome of fracture in patients with T2DM treated with SGLT2 inhibitors. Pairwise and network meta-analyses, as well as a cumulative meta-analysis, were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: A total of 38 eligible RCTs (10 canagliflozin, 15 dapagliflozin and 13 empagliflozin) involving 30 384 patients, with follow-ups ranging from 24 to 160 weeks, were included. The fracture event rates were 1.59% in the SGLT2 inhibitor groups and 1.56% in the control groups. The incidence of fracture events was similar among these three SGLT2 inhibitor groups. Compared with placebo, canagliflozin (OR 1.15; 95% CI 0.71-1.88), dapagliflozin (OR 0.68; 95% CI 0.37-1.25) and empagliflozin (OR 0.93; 95% CI 0.74-1.18) were not significantly associated with an increased risk of fracture. Our cumulative meta-analysis indicated the robustness of the null findings with regard to SGLT2 inhibitors., Conclusions: Our meta-analysis based on available RCT data does not support the harmful effect of SGLT2 inhibitors on fractures, although future safety monitoring from RCTs and real-world data with detailed information on bone health is warranted., (© 2016 John Wiley & Sons Ltd.)

Caspases are the key mediators of apoptotic cell death via their proteolytic activity. When caspases are activated in cells to levels detectable by available technologies, apoptosis is generally assumed to occur shortly thereafter. Caspases can cleave many functional and structural components to cause rapid and complete cell destruction within a few minutes. However, accumulating evidence indicates that in normal healthy cells the same caspases have other functions, presumably at lower enzymatic levels. Studies of non-apoptotic caspase activity have been hampered by difficulties with detecting low levels of caspase activity and with tracking ultimate cell fate in vivo. Here, we illustrate the use of an ultrasensitive caspase reporter, CaspaseTracker, which permanently labels cells that have experienced caspase activity in whole animals. This in vivo dual color CaspaseTracker biosensor for Drosophila melanogaster transiently expresses red fluorescent protein (RFP) to indicate recent or on-going caspase activity, and permanently expresses green fluorescent protein (GFP) in cells that have experienced caspase activity at any time in the past yet did not die. Importantly, this caspase-dependent in vivo biosensor readily reveals the presence of non-apoptotic caspase activity in the tissues of organ systems throughout the adult fly. This is demonstrated using whole mount dissections of individual flies to detect biosensor activity in healthy cells throughout the brain, gut, malpighian tubules, cardia, ovary ducts and other tissues. CaspaseTracker detects non-apoptotic caspase activity in long-lived cells, as biosensor activity is detected in adult neurons and in other tissues at least 10 days after caspase activation. This biosensor serves as an important tool to uncover the roles and molecular mechanisms of non-apoptotic caspase activity in live animals.

Two new amicoumacins, named Damxungmacin A ( 1 ) and B ( 2 ), were isolated from the culture broth of a soil-derived bacterium Bacillus subtilis XZ-7. Their chemical structures were elucidated by spectroscopic studies (UV, IR, NMR and HR-ESI-MS). Compound 1 possessed a 1,4-diazabicyclo[2.2.1]heptane-2-one ring system in its structure, which was reported for the first time, while 2 had a 1-acetylmorpholine-3-one moiety, which was naturally rare. Compound 1 exhibited moderate to weak cytotoxic activities against three human tumor cell lines (A549, HCT116 and HepG2) with IC 50 values of 13.33, 14.34 and 13.64 μM, respectively. Meanwhile, compound 1 showed weak antibacterial activities against some strains of Staphylococcus epidermidis , while compound 2 at 16 μg/mL did not show antibacterial activity.

Objective: To understand the HIV transmission and associated factors in newly reported HIV infected couples before diagnosis. Methods: The information about newly reported HIV infected couples in Yunnan, Guangxi, Sichuan, Henan and Xinjiang provinces (autonomous region) were collected from National HIV/AIDS Information System from 2011 to 2014. The infection order of the sero-concordant couples were determined. Logistic regression model was used to analyze the HIV transmission between couples and identify the associated factors. Cochran-Armitage trend analysis was conducted to understand the annual sero-concordant couple proportion. Results: A total of 48 931 HIV cases in couples were included in this study, among whom 12 051(24.6%) were sero-concordant couples, indicating HIV transmissions occurred between them. Multivariate logistic regression analysis showed that those who were females ( OR =1.98, 95% CI : 1.89-2.08), aged >45 years (45-59 yrs: OR =1.32, 95% CI : 1.23-1.42; >60 yrs: OR =1.72, 95% CI : 1.58-1.86), had educational level of middle school education or below (illiteracy and primary school: OR =1.33, 95% CI : 1.23-1.44; middle school: OR =1.19, 95% CI : 1.10-1.28), were farmers or migrate workers ( OR =1.23, 95% CI : 1.17-1.30), were infected through injecting drug use or heterosexual intercourse (injecting drug use: OR =1.33, 95% CI : 1.03-1.72; heterosexual intercourse: OR =3.65, 95% CI : 2.89-4.61), had CD 4 + T cells of <500 cells/μl (<200 cells/μl: OR =5.05, 95% CI : 4.62-5.52; 200-349 cells/μl: OR =3.58, 95% CI : 3.26-3.93; 350-500 cells/μl: OR =2.14, 95% CI : 1.94-2.36), reported unprotected sexual behaviors ( OR =1.56, 95% CI : 1.49-1.64), were more likely to infect their couples before diagnosis. The HIV transmission proportion between couples before diagnosis decreased significantly from 28.9% (2 631/9 102) in 2011 to 25.5% (3 009/11 787) in 2014 among those infected through heterosexual intercourse. Conclusion: The proportion of HIV transmission between couples before diagnosis varied among different populations. Behavior intervention and early HIV test promoting are needed to prevent HIV transmission between couples before diagnosis in populations at high risk for HIV infection. HIV infection cases should be included in the HIV care system after diagnosis as early as possible.

Formation of brominated disinfection by-products (DBPs) from bromide and natural organic matter upon chlorination imposes health risks to drinking water users. In this study, capacitive deionization (CDI) was evaluated as a potential process for DBP precursor removal. Synthetic humic acid and bromide containing saline water was used as model water prior to CDI treatment. Batch experiments were conducted at cell voltages of 0.6-, 0.9-, and 1.2V to study the influence of CDI on the ratio of bromide and dissolved organic carbon, bromine substitution factor, and DBP formation potential (FP). Results showed beneficial aspects of CDI on reducing the levels of these parameters. A maximum DBPFP removal from 1510 to 1160μg/L was observed at the cell voltage of 0.6V. For the removed DBPFP, electro-adsorption played a greater role than physical adsorption. However, it is also noted that there could be electrochemical oxidations that led to reduction of humic content and formation of new dichloroacetic acid precursors at high cell voltages. Because of the potential of CDI on reducing health risks from the formation of less brominated DBPs upon subsequent chlorination, it can be considered as a potential technology for DBP control in drinking water treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Despite recent progress in the development of hepatitis C virus (HCV) inhibitors, cost-effective antiviral drugs, especially among the patients receiving liver transplantations, are still awaited. Schisandra is a traditional medicinal herb used to treat a range of liver disorders including hepatitis for thousands of years in China. To isolate the bioactive compounds of schisandra for the treatment of HCV infection, we screened a schisandra-extracts library and identified a tetracyclic triterpenoid, schizandronic acid (SZA), as a novel HCV entry inhibitor. Our findings suggested that SZA potently inhibited pan-HCV genotype entry into hepatoma cells and primary human hepatocytes without interfering virus binding on cell surface or internalization. However, virion-cell fusion process was impaired in the presence of SZA, along with the increased host membrane fluidity. We also found that SZA inhibited the spread of HCV to the neighboring cells, and combinations of SZA with interferon or telaprevir resulted in additive synergistic effect against HCV. Additionally, SZA diminished the establishment of HCV infection in vivo. The SZA target is different from conventional direct-acting antiviral agents, therefore, SZA is a potential therapeutic compound for the development of effective HCV entry inhibitors, especially for patients who need to prevent HCV reinfection during the course of liver transplantations.

A number of acute or repeated stimuli can induce expression of DeltaFosB (ΔFosB), a transcription factor derived from the fosB gene (an osteosarcoma viral oncogene) via alternative splicing. ΔFosB protein is currently viewed as a 'molecular switch' to repeated stimuli that gradually converts acute responses into relatively stable adaptations underlying long-term neural and behavioral plasticity. ΔFosB has received extensive attention in drug addition, depression, and stress adaptation, but changes in ΔFosB protein expression during pain is not fully understood. In this study we explored ΔFosB expression in the medial prefrontal cortex (mPFC) of rats experiencing chronic or acute stress-induced pain. Our data reveal that chronic pain induced by neonatal colorectal distension, chronic constriction injury (CCI) of the sciatic nerve, or maternal separation was associated with an increase in ΔfosB protein expression in mPFC, but acute application of acetic acid or zymosan did not alter the ΔFosB protein expression. ΔFosB expression in the rat visual cortex, a non pain-related brain region, did not change in response to (CCI) of the sciatic nerve and acetic acid treatment. In conclusion, our results indicate that ΔFosB protein expression is significantly elevated in rats that have experienced chronic pain and stress, but not acute pain. The ΔFosB protein may serve as an important transcription factor for chronic stress-induced pain. Further research is needed to improve the understanding of both the upstream signaling leading to ΔFosB protein expression as well as the regulation of ΔFosB gene expression in cortical neurons.

Ubiquitin-specific protease 22 (USP22) aberrance has been implicated in several malignancies; however, whether USP22 plays a role in anaplastic thyroid carcinoma (ATC) remains unclear. Here, we report that USP22 expression is highly elevated in ATC tissues, which positively correlated with tumor size, extracapsular invasion, clinical stages, and poor prognosis of ATC patients. In vitro assays showed that USP22 depletion suppressed ATC cell survival and proliferation by decreasing Rb phosphorylation and cyclin D2, inactivating Akt, and simultaneously upregulating Rb; USP22 silencing restrained cell migration and invasion by inhibiting epithelial-mesenchymal transition; USP22 knockdown promoted mitochondrion- mediated and caspase-dependent apoptosis by upregulating Bax and Bid and promoting caspase-3 activation. Consistent with in vitro findings, downregulation of USP22 in ATC cells impeded tumor growth and lung metastasis in vivo. These results raise the applicability for USP22 as a useful predictor of ATC prognosis and a potential therapeutic target for ATC., Competing Interests: The authors declare that they have no competing interests.

Although much progress has been made in antiviral agents against hepatitis C virus (HCV) in recent years, novel HCV inhibitors with improved efficacy, optimized treatment duration and more affordable prices are still urgently needed. Here, we report the identification of a natural plant-derived lignan, trachelogenin (TGN), as a potent entry inhibitor of HCV without genotype specificity, and with low cytotoxicity. TGN was extracted and purified from Caulis trachelospermi, a traditional Chinese herb with anti-inflammatory and analgesic effects. A crucial function of TGN was the inhibition of HCV entry during a post-binding step without affecting virus replication, translation, assembly and release. TGN blocked virus infection by interfering with the normal interactions between HCV glycoprotein E2 and the host entry factor CD81, which are key processes for valid virus entry. In addition, TGN diminished HCV cell-to-cell spread and exhibited additional synergistic effects when combined with IFN or telaprevir. In conclusion, this study highlights the effect of a novel HCV entry inhibitor, TGN, which has a target that differs from those of the current antiviral agents. Therefore, TGN is a potential candidate for future cocktail therapies to treat HCV-infected patients.

A biologically activate carbon (BAC) filter was continuously operated on site for the treatment of haloacetic acids (HAAs) in an outdoor swimming pool at an average empty bed contact time (EBCT) of 5.8 min. Results showed that BAC filtration was a viable technology for direct removal of HAAs from the pool water with a nominal efficiency of 57.7% by the filter while the chlorine residuals were 1.71 ± 0.90 mg/L during the study. THMs and TOC were not removed and thus were not considered as indicators of the effectiveness of BAC filtration. Increased EBCT in the range of 4.5 and 6.4 min led to improved HAA removal performance, which could be best fit by a logarithmic regression model. BAC filtration also affected the HAA speciation by removing more dichloroacetic acid (DCAA) than trichloroacetic acid (TCAA), resulting in a lower ratio of DCAA/TCAA in the filtered effluent. However, the observation of an overall constant ratio could be attributable to a complex formation and degradation mechanism occurring in swimming pools., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Patients without diabetic retinopathy (DR) represent a large proportion of the caseload seen by the DR screening service so reliable recognition of the absence of DR in digital fundus images (DFIs) is a prime focus of automated DR screening research. We investigate the use of a novel automated DR detection algorithm to assess retinal DFIs for absence of DR. A retrospective, masked, and controlled image-based study was undertaken. 17,850 DFIs of patients from six different countries were assessed for DR by the automated system and by human graders. The system's performance was compared across DFIs from the different countries/racial groups. The sensitivities for detection of DR by the automated system were Kenya 92.8%, Botswana 90.1%, Norway 93.5%, Mongolia 91.3%, China 91.9%, and UK 90.1%. The specificities were Kenya 82.7%, Botswana 83.2%, Norway 81.3%, Mongolia 82.5%, China 83.0%, and UK 79%. There was little variability in the calculated sensitivities and specificities across the six different countries involved in the study. These data suggest the possible scalability of an automated DR detection platform that enables rapid identification of patients without DR across a wide range of races., Competing Interests: The authors declare that they have no conflict of interests.

We aimed to evaluate dendritic cell (DC) tumor vaccines for preventing liver cancer recurrence and metastasis. DCs were induced from mononuclear cells in the peripheral blood with recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) and recombinant human interleukin 4 (rhIL-4), followed by sensitization with lysis of autologous liver cancer cells. One hundred and sixty patients with hepatocellular carcinoma were randomly divided into two groups of 80. One group was treated postoperatively with six cycles of the DC tumor vaccine. The other group was treated postoperatively with six cycles of FOLFOX 6, beginning 1 week after surgery. After treatment with DC tumor vaccines, the levels of CD3+, CD4+, and CD8+, the ratio of CD4+ to CD8+ DC, and the serum levels of IL-12 and IFN-γ were significantly increased both in comparison to the pre-treatment levels (P < 0.001) and to the chemotherapy group (P < 0.001). After a postoperative follow-up of 18 months, the metastatic recurrence rate in the DC tumor vaccine group was significantly lower than that in the chemotherapy group (17.50 vs 48.75%, P < 0.005), and the survival rate of the patients in the DC tumor vaccine group was higher than that of the chemotherapy treatment group (86.25 vs 52.50%, P < 0.005). Treatment with DC tumor vaccines was safe and feasible. It can enhance the immunity of the patients, reduce the rates of metastasis and recurrence, and improve survival rates. This is a promising treatment for the prevention of postoperative recurrence in patients with liver cancer.

In terms of inconsistent conclusions across all relevant randomized controlled trials (RCTs) and available meta-analyses, we aimed to use a meta-analysis and trial sequential analysis (TSA) to evaluate whether clinical utility of a genotype-guided warfarin initiation dosing algorithm could be better than that of a standard therapy regimen, and whether currently relevant evidence could be reliable and conclusive. Overall, 11 eligible RCTs involving 2677 patients were included for further analyses. Compared with fixed dose or clinically adjusted warfarin initiation dosing regimens, genotype-guided algorithms significantly increased time in therapeutic range, shortened time to first therapeutic international normalized ratio (INR) and time to stable doses, but did not show any marked improvements in excessive anticoagulation, bleeding events, thromboembolism, or all-cause mortality. Subgroup analyses revealed that, genotype-guided algorithms showed better control in the outcomes of time in therapeutic range or excessive anticoagulation than fixed-dose regimens rather than clinically adjusted regimens. Except for excessive anticoagulation, currently available evidence of all other outcomes was unreliable and inconclusive as determined with TSA. Our findings suggest that genotype-guided warfarin initiation dosing algorithms have superiority in the improvement of surrogate quality markers for anticoagulation control, but that this does not translate into statistically significant differences in clinical outcomes, which is largely because of the insufficient sample size in the RCTs analyzed.

Novel nanocomposites of carbon nanotubes supported porous VO(x)N(y) nonoribbons (VO(x)N(y)-CNTs) have been synthesized by the annealing of the sol-gel mixture of CNTs and V2O5 under NH3 atmosphere as well as the ageing process in air. Besides the morphological and structural characterizations revealed by TEM, SEAD, EDS, XRD and XPS measurements, typical electrochemical tests including cyclic voltammetry (CV), rotating disk electrode (RDE) and chronoamperometry have been employed to determine the oxygen reduction reaction (ORR) performance of VO(x)N(y)-CNTs. Inspiringly, the results indicate that VO(x)N(y)-CNTs catalyst exhibits a 0.4 mA/cm(2) larger diffusion-limited current density, a 0.10  V smaller onset potential value, a 10.73% less of ORR current decay and an excellent methanol-tolerance compared with commercial Pt/C catalyst. Therefore, we have reasonable grounds to believe that this new VO(x)N(y)-CNTs nanocomposites can be regarded as a promising non-precious methanol-tolerant ORR catalyst candidate for alkaline fuel cells.

Objective: To screen out blood-stasis syndrome (BSS)-associated microRNA and therefore determine the possible target for treating hypertension., Methods: A high-energy sequencing method and digital gene expression sequencing theory were adopted to sequence microRNA (miRNA) and messenger RNA (mRNA), and to determine differential expression in human umbilical vein endothelial cells incubated with serum samples from hypertension patients with or without BSS, and healthy controls. The results were confirmed using gene prediction software., Results: A total of 13 miRNAs and 11 mRNAs showed statistical difference both in the BSS/normal groups and BSS/non-BSS groups, respectively. Four pairs of target mRNA/miRNA were identified: FRMD4A/hsa-miR-34a, MAP3K14/hsa-miR-34a, PER1/hsa-miR-34a, and FGF2/hsa-miR-132., Conclusion: Four mRNA/miRNA pairs mentioned above seem to be involved in pathogenesis and maintenance of hypertension with BSS.

Objective: To investigate the association between cyclo-oxygenase-2 (COX-2) polymorphism and the risk of hepatocellular carcinoma (HCC) development., Design: Systematic review and meta-analysis of COX-2 polymorphism and risk of HCC development among people with or without HCC., Data Sources: EMBASE, PubMed, Public Library of Science, SCOPUS, Web of Knowledge and Chinese National Knowledge Infrastructure were searched for all clinical and experimental case-control studies of COX-2 polymorphism and HCC risk. Studies published up to March 2015 were included., Review Method: Ten studies were included for data extraction, which were mainly from Asian countries., Results: 2538 people with HCC and 3714 without HCC were found to satisfy the inclusion criteria and included in the review. The associations of specific genotypes in the eight polymorphic variants of COX-2 and the risk of HCC development were analysed. GG genotype at the A-1195G polymorphism may be associated with a reduced risk of HCC development: the OR across all studies was 0.87 (95% CI 0.75 to 1.02) for the G allele versus the A allele, 0.72 (0.53 to 0.97) for GG versus AA, 0.72 (0.57 to 0.92) for GG versus GA+AA and 1.05 (0.77 to 1.44) for AA versus GA+GG. Similar results were found when the meta-analysis was repeated separately for the Chinese subgroup. However, more reliable data are needed to demonstrate associations between variants in G-765C, T+8473C, A-1290G, G-899C and introns 1, 5 and 6 polymorphisms and the risk of HCC development., Conclusions: Only the COX-2 A-1195G gene polymorphism may be associated with a decreased risk of HCC development. These conclusions should be verified in further studies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To investigate the influence of CD117 expression on response of multiple myeloma patients to chemo-therapy., Methods: A total of 65 cases of newly diagnosed multiple myeloma in our hospital from 2011 to 2013 were enrolled in this study. Cytogenetic abnormalities and immunophenotype were detected by using fluorescence in situ hybridization and flow cytometry before chemotherapy. The therapeutic efficacy of patients was evaluated after 4 cycles of PAD or TAD regimen., Results: The positive rates of 1q21 amplification, RB1: 13q14 deletion, D13S319: 13q14.3 deletion, IgH: 14q32 rearrangement and p53: 17p13 deletion were 32.2%, 40%, 40%, 20% and 3.1% respectively; the positive rates of CD38, CD138, CD56, CD117, CD20 were respectively 100%, 100%, 60%, 20%, 10.8%; the positive rates of CD19 and CD10 were 4.6% and 4.6% respectively; the positive CD22, CD7, CD5, CD103 did not found in any patients. The therapeutic efficacy of CD117⁻ patients was better than that of CD117⁺ patients (P < 0.05), there was no correlation of the remaining indicators with efficacy; the proportion of CD117⁺ patients with β2-microglobulin ≥ 5.5 mg/L was significantly higher than that of CD117⁻ patients (P < 0.05); the rest of baseline data had no significant difference (P > 0.05)., Conclusion: CD117 can be used as an indicator for evaluating efficacy of patients with newly diagnosed multiple myeloma.

There is increasing concern regarding the adverse health effects of polychlorinated naphthalenes (PCNs). The metabolic degradation of 1,4-dichloronaphthalene (1,4-DCN) as a model PCN, was studied using a strain of Pseudomonas sp. HY. The metabolites were analyzed by gas chromatography-mass spectrometry (GC-MS). A series of metabolites including dihydroxy-dichloro-naphthalene, epoxy-dichlorinated naphthalene, dichlorinated naphthol, and dichlorinated salicylic acid were identified. The time-concentration plots of the degradation curves of 1,4-DCN was also obtained from the experiments, which set the initial concentration of 1,4-DCN to 10 mg/L and 20 mg/L, respectively. The results showed that 98% removal could be achieved within 48 h at an initial 1,4-DCN concentration of 10 mg/L. Nevertheless, it took 144 h to reach the same degradation efficiency at an initial concentration of 20 mg/L. The degradation of 1,4-DCN may not remove the chloride ions during the processes and the metabolites may not benefit the bacterial growth. The research suggests a metabolic pathway of 1,4-DCN, which is critical for the treatment of this compound through biological processes.

This study investigated the effects of CpG ODN1826 plus radiotherapy (RT) on tumor growth and angiogenesis of subcutaneous tumor in a rat model. Four treatment groups were tested in which rats were injected with 100 μL CpG ODN1826 (1 μg/μL) or 100 μL vehicle, with and without exposure to 8 Gy after 2 h. At 7 days after inoculation of lung cancer cells, drugs were injected in the tumor and radiation was administered over 5 days, after which the rate of tumor inhibition was calculated. Expression of VEGF-C in tumor tissue was seen in 10, 50, 80, and 100% of tumors in the CpG ODN1826 + RT, CpG ODN1826, vehicle + RT, and vehicle alone groups, respectively, while positive expression of NRP-1 was seen in 10, 40, 90, and 100% of tumors. The decreases in expression of VEGF-C mRNA in the CpG ODN1826 + RT and CpG ODN1826 groups compared with the NS + RT and NS groups were significant (P < 0.01), as were the decreases in NRP-1 mRNA in the CpG ODN1826 + RT group compared with the CpG ODN1826 group (P < 0.01). Thus, CpG ODN1826 can significantly inhibit tumor growth in a rat model, the mechanism of which may be related to inhibition of the expression of VEGF-C and NRP-1, which have an inhibitory effect on angiogenesis.

Geotrichum capitatum infection has a very low incidence rate with atypical clinical symptoms, making diagnosis difficult, and it has a poor prognosis. The incidence is even more rare in China. This paper reports the first case of infection caused by G. capitatum during bone marrow suppression after chemotherapy in a Chinese patient with acute lymphoblastic leukemia. In addition, it reports a systematic literature review of diagnosis and treatment. The patient with acute lymphoblastic leukemia was confirmed to be infected with G. capitatum, involving lung, liver and skin, through a blood culture test. Caspofungin, amphotericin B loposome, and a combination therapy of amphotericin B liposome and voriconazole were used in succession for treatment. Despite normal body temperature and a slight improvement of clinical symptoms with the combination therapy treatment, the patient died 40 days after chemotherapy due to heart and lung failure.

Batch nitrification tests were conducted with sludge and wastewater streams obtained from field implementations to evaluate nitrification inhibition and efficiency of a nitrifiers bioaugmentation technology at full-scale municipal wastewater treatment plants (WWTPs). The results showed that the substrate organic carbon and pH of wastewater streams were inhibitory factors to nitrification and the low pH was the cause of the WWTP experiencing poor nitrification. An ammonia-nitrogen removal rate of 0.21mg-N/gMLVSS-h was observed at pH 6.5, while the rate increased to 0.54mg-N/gMLVSS-h with an introduction of 6% bioaugmented nitrifiers, indicating that the integrated side-stream nitrifiers bioaugmentation process was beneficial in improving nitrification efficiency, even under low pH conditions not conducive to nitrification. The study provides new insights into effective upgrading of municipal WWTPs exposed to poor nitrification., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Two-dimensional transition metal dichalcogenides (TMDCs) such as molybdenum sulfide MoS2 and tungsten sulfide WSe2 have potential applications in electronics because they exhibit high on-off current ratios and distinctive electro-optical properties. Spatially connected TMDC lateral heterojunctions are key components for constructing monolayer p-n rectifying diodes, light-emitting diodes, photovoltaic devices, and bipolar junction transistors. However, such structures are not readily prepared via the layer-stacking techniques, and direct growth favors the thermodynamically preferred TMDC alloys. We report the two-step epitaxial growth of lateral WSe2-MoS2 heterojunction, where the edge of WSe2 induces the epitaxial MoS2 growth despite a large lattice mismatch. The epitaxial growth process offers a controllable method to obtain lateral heterojunction with an atomically sharp interface., (Copyright © 2015, American Association for the Advancement of Science.)

A novel VN/C nanostructure consisting of VN nanoparticles and graphite-dominant carbon layers is synthesized by nitridation of V2O5 using melamine as reductant under inert atmosphere. High crystalline VN nanoparticles are observed to be uniformly distributed in carbon layers with an average size of ca13.45 nm. Moreover, the electrocatalytic performance of VN/C towards oxygen reduction reaction (ORR) in alkaline electrolyte is fascinating. The results show that VN/C has a considerable ORR activity, including a 75 percent value of the diffusion-limited current density and a 0.11 V smaller value about the onset potential with respect to Pt/C catalyst. Moreover, the excellent methanol-tolerance performance of VN/C has also been verified with 3 M methanol. Combined with the competitive prices, this VN/C nanocomposite can serve as an appropriate non-precious methanol-tolerant ORR catalyst for alkaline fuel cells.

Our previous study reported that retinoic acid induced 16 (RAI16) could enhance tumorigenesis in hepatocellular carcinoma (HCC). However, the cellular functions of RAI16 are still unclear. In this study, by immunoprecipitation and tandem (MS/MS) mass spectrometry analysis, we identified that RAI16 interacted with the type II regulatory subunit of PKA (PKA-RIIα), acting as a novel protein kinase A anchoring protein (AKAP). In addition, RAI16 also interacted with heat shock protein 70 (HSP70) and 14-3-3θ. Further studies indicated that RAI16 mediated PKA phosphorylation of HSP70 at serine 486, resulting in anti-apoptosis events. RAI16 was also phosphorylated by the anchored PKA at serine 325, which promoted the recruitment of 14-3-3θ, which, in turn, inhibited RAI16 mediated PKA phosphorylation of HSP70. These findings offer mechanism insight into RAI16 mediated anti-apoptosis signaling in HCC.

Background and Objective: The association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients., Methods: Studies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1., Results: Seven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation., Conclusion: Based on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).