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Based on phase space reconstruction theory, the root mean square error is used as a quantitative criterion for identifying the appropriate embedding dimension and time step and selecting the optimal configuration for these factors. The phase space is then reconstructed, and the convergent cross-mapping algorithm is applied to analyse the causality between time series. The causality among the variables in the Lorenz equation is first discussed, and the response of this causality to the integration step of numerical solutions to the Lorenz equation is analyzed. We conclude that changes in the integration step do not alter the causality but will affect its strength. Variables X and Y drive each other, whereas variable Z drives variables X and Y in a unidirectional manner. Second, meteorological data from 1948-2022 are used to analyse the effect of the Southern Hemisphere annular mode on the East Asian summer monsoon index and surface air temperature driving capacity. From a dynamic perspective, it is concluded that the Southern Hemisphere annular mode is the driving factor affecting the East Asian summer monsoon index and surface air temperature. Based on ideal test results and the observation data, the collaborative selection of the embedding dimension and time step is more reliable in terms of determining causality. This provides the ability to determine causality between climate indices and theoretically guarantees the selection of climate predictors.

Plant-pollinator networks have been repeatedly reported as cumulative ones that are described with >1 years observations. However, such cumulative networks are composed of pairwise interactions recorded at different periods, and thus may not be able to reflect the reality of species interactions in nature (e.g., early-flowering plants typically do not compete for shared pollinators with late-flowering plants, but they are assumed to do so in accumulated networks). Here, we examine the monthly sampling structure of an alpine plant-pollinator bipartite network over a two-year period to determine whether relative species abundance and species traits better explain the network structure of monthly networks than yearly ones. Although community composition and species abundance varied from one month to another, the monthly networks (as well as the yearly networks described with annual pooled data) had a highly nested structure, in which specialists directly interact with generalist partners. Moreover, relative species abundance predicted the nestedness in both the monthly and yearly networks and accounted for a statistically significant percentage of the variation (i.e., 20%-44%) in the pairwise interactions of monthly networks, but not yearly networks. The combination of relative species abundance and species traits (but not species traits only) showed a similar prediction power in terms of both network nestedness and pairwise interaction frequencies. Considering the previously recognized structural pattern and associated mechanisms of plant-pollinator networks, we propose that relative species abundance may be an important factor influencing both nestedness and interaction frequency of pollination networks.

Proteins were extracted from perilla (Perilla frutescens L. Britton) seed by-products and hydrolyzed with an alkaline protease. Antioxidant peptides were purified from the hydrolysate by size-exclusion chromatography and RP-HPLC. Two peptides with strong antioxidant activity were identified as Tyr-Leu (YL) and Phe-Tyr (FY) with the molecular mass of 294.33 Da and 328.33 Da, respectively. Synthesized YL and FY efficiently quenched free radicals (DPPH, ABTS and hydroxyl radicals) and showed high oxygen radical absorbance capacity. The two peptides also inhibited lipid peroxidation in the rat liver. Furthermore, YL and FY could protect HepG-2 cells against hydrogen peroxide-induced oxidative damage without cytotoxicity. Based on the structure-activity analysis, the Tyr residue was crucial for the antioxidant activity of YL and FY. The results indicate that the protein hydrolysate from perilla seed by-products possessed potent biological activity and can be utilized to develop health-related nutraceutical ingredients.

To investigate the regulation of K17 expression by the pro-inflammatory cytokine IL-22 in keratinocytes and its important role in our previously hypothesized "K17/T cell/cytokine autoimmune loop" in psoriasis.K17 expression was examined in the IL-22-treated keratinocytes by real-time quantitative PCR, ELISA, Western blot and Immunofluorescence. In addition, the signaling pathways involved in K17 regulation were investigated with related inhibitors and siRNAs. In addition, K17 expression was examined in the epidermis of IL-22-injected mouse skin.IL-22-induced K17 expression was confirmed in keratinocytes and the epidermis of IL-22-injected mouse skin at both mRNA and protein levels, which is an important complement to the autoimmune loop. We further investigated the regulatory mechanisms and found that both STAT3 and ERK1/2 were involved in the up-regulation of K17 expression induced by IL-22.IL-22 up-regulates K17 expression in keratinocytes in a dose-dependent manner through STAT3- and ERK1/2-dependent mechanisms. These findings indicated that IL-22 was also involved in the K17/T cell/cytokine autoimmune loop and may play an important role in the progression of psoriasis.

Network density is an important attribute that affects the efficiency of innovation networks. However, the understanding of how network density affects the innovation efficiency of innovation networks is still unclear and even controversial. This paper uses a multiagent simulation method to study this problem. First, an innovation simulation model is established to describe the generation process of innovations in the context of network innovation, and a classical random network model is used to generate a test set of structures with different network densities. Then, the innovation model is run on the test set of networks to obtain the innovation efficiency of the structures with different network densities. The result shows that for explorative innovation, high network density is more conducive to improving innovation efficiency, and for exploitative innovation, low network density is more conducive to improving innovation efficiency. However, when network density is small enough to destroy network connectivity, it will lead to a large risk of innovation failure. Finally, the reasons for the results are further analyzed, and the theoretical and practical significance of the conclusions are discussed.

As countries underwent the initiation, peak, post-peak, and early vaccination stages of COVID-19, the changing risk perception, coping behaviors and corresponding psychological stress experienced by the public over time was rarely reported. We conducted a national scale panel study using social-psychological data collected from 5,983 questionnaires to investigate the interactions between anxiety level, risk perception and coping behavior during different stages of COVID-19 in China. We found that sustained perceiving worries of being infected, first due to domestic and then global pandemic, contributed to the persistent high proportion of respondents with anxiety disorders which even gradually increased over time (56.1% during initiation to 60.4% during early vaccination). Gender was the strongest predictor of anxiety at all stages, with females having less confidence in COVID-19 control and always suffering from much higher anxiety levels than males even during the post peak stage. Excessive protective behavior and frequency of access to COVID-related news also contributed to public anxiety. Additionally, public risk perception was significantly associated with their willingness to vaccinate. The findings verify the feasibility of taking stage-specific and gender-based risk communication strategies to alleviate the pandemic-related public anxiety and promote vaccination by influencing public risk perception and guiding coping behaviors.

Background/aimsIsoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown.MethodsIn current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects.ResultsIATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (PConclusionsIATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

Postpartum depression (PPD) is one of the mental health complications that may arise following childbirth. This cross-sectional study explores the association between socioeconomic factors and PPD literacy with PPD incidence in 350 participants (mean age: 30.58±4.72 years) at one to six months postpartum, who attended the Kuala Lumpur Health Clinic from May to October 2020. PPD incidence and literacy were assessed using the validated Malay versions of the Edinburgh Postpartum Depression Scale (EPDS) and the Postpartum Depression Literacy Scale (PoDLiS), respectively. The participants’ socioeconomic characteristics were collected using a self-administered questionnaire. Chi-square tests were performed to determine the association between these factors and PPD incidence. Binary logistic regression models were used to determine the odds ratios (OR). The incidence of postpartum depressive symptoms was 14.29%. Those with low household income were twice likely to have PPD symptoms (OR:2.58, 95% CI:1.23–5.19; p = 0.01) than those with higher incomes. Unemployment (i.e., participants who were housewives/homemakers) was associated with higher PPD incidence (Χ2(2, 350) = 6.97, p = 0.03), but it was not a significant PPD predictor. In conclusion, PPD incidence in the sample of Kuala Lumpur postpartum mothers is significantly associated with low household income. Other socioeconomic characteristics, including PPD literacy, were not significant predictors of PPD incidence.

Cancer is a life-threatening disease, and the challenges in accepting the diagnosis can bring a devastating emotional impact on the patient's mental and psychological wellbeing. Issues related to illness acceptance among cancer patients are not well studied in Malaysia. To date, the Acceptance of Illness Scale has not been translated to the Malay language (Bahasa Malaysia) nor validated for use in the oncology setting. The objective of the study is to translate, validate and determine the reliability of the Bahasa Malaysia version of the Acceptance of Illness Scale among Malaysian patients with cancer. A total of 129 patients newly diagnosed with cancer were consecutively sampled and the scale was administered via face-to-face interviews. A pilot test (n = 30) was conducted and test-retest reliability was determined. The Bartlett Test of Sphericity was statistically significantly (p

Cadmium (Cd) is a toxic non-essential element, while calcium (Ca) is an essential element with high chemical similarity to Cd. Dietary intake is the major Cd exposure pathway for non-smokers. A multi-concentration dietary intervention experiment was designed to explore the optimum concentration of Ca in diet with obvious protective effects against the toxicity of livers and kidneys induced by Cd in mice. The mice were divided into six groups with different concentrations of Cd and Ca in their food: control-group (no Cd or Ca), Ca-group (100 g/kg Ca, without Cd), Cd-group (2 mg/kg Cd, without Ca), CaL+Cd-group (2 mg/kg Cd, 2 g/kg Ca), CaM+Cd-group (2 mg/kg Cd, 20 g/kg Ca) and CaH+Cd-group (2 mg/kg Cd, 100 g/kg Ca). The organ indexes, oxidative stress biomarkers, lesions and Cd concentrations were detected after a 30-day exposure period. Results showed that serum Aspartate Aminotransferase (AST) level in CaH+Cd-group was significantly lower than that in Cd-group, while close to that in control-group. The contents of Serum Blood Urea Nitrogen (BUN) in different groups showed the same trend. Concentrations of all oxidative stress biomarkers (GSH-Px, SOD, CAT, GSH and MDA) in CaH+Cd-group were close to the normal levels of control-group while significantly different from those in Cd-group. The only exception was the Malondialdehyde (MDA) levels in kidneys. This study suggests that Ca plays a protective role in relieving the Cd-induced toxicity of livers and kidneys and a concentration of 100 g/kg for Ca in diet showed the best protective effects. These findings could provide a clue for further studies concerning human diet intervention for Cd control.

Imaging techniques based on fluorescence and bioluminescence have been important tools in visualizing tumor progression and studying the effect of drugs and immunotherapies on tumor immune microenvironment in animal models of cancer. However, transgenic expression of foreign proteins may induce immune responses in immunocompetent syngeneic tumor transplant models and augment the efficacy of experimental drugs. In this study, we show that the growth rate of Lewis lung carcinoma (LL/2) tumors was reduced after transduction of tdTomato and luciferase (tdTomato/Luc) compared to the parental cell line. tdTomato/Luc expression by LL/2 cells altered the tumor microenvironment by increasing tumor-infiltrating lymphocytes (TILs) while inhibiting tumor-induced myeloid-derived suppressor cells (MDSCs). Interestingly, tdTomato/Luc expression did not alter the response of LL/2 tumors to anti-PD-1 and anti-CTLA-4 antibodies. These results suggest that the use of tdTomato/Luc-transduced cancer cells to conduct studies in immune competent mice may lead to cell-extrinsic tdTomato/Luc-induced alterations in tumor growth and tumor immune microenvironment that need to be taken into consideration when evaluating the efficacy of anti-cancer drugs and vaccines in immunocompetent animal models.

In this study, the Pb2+ biosorption potential of live and dead biosorbents of the hydrocarbon-degrading strain Rhodococcus sp. HX-2 was analyzed. Optimal biosorption conditions were determined via single factor optimization, which were as follows: temperature, 25°C; pH, 5.0, and biosorbent dose, 0.75 g L-1. A response surface software (Design Expert 10.0) was used to analyze optimal biosorption conditions. The biosorption data for live and dead biosorbents were suitable for the Freundlich model at a Pb2+ concentration of 200 mg L-1. At this same concentration, the maximum biosorption capacity was 88.74 mg g-1 (0.428 mmol g-1) for live biosorbents and 125.5 mg g-1 (0.606 mmol g-1) for dead biosorbents. Moreover, in comparison with the pseudo-first-order model, the pseudo-second-order model seemed better to depict the biosorption process. Dead biosorbents seemed to have lower binding strength than live biosorbents, showing a higher desorption capacity at pH 1.0. The order of influence of competitive metal ions on Pb2+ adsorption was Cu2+ > Cd2+ > Ni+. Fourier-transform infrared spectroscopy analyses revealed that several functional groups were involved in the biosorption process of dead biosorbents. Scanning electron microscopy showed that Pb2+ attached to the surface of dead biosorbents more readily than on the surface of live biosorbents, whereas transmission electron microscopy confirmed the transfer of biosorbed Pb2+ into the cells in the case of both live and dead biosorbents. It can thus be concluded that dead biosorbents are better than live biosorbents for Pb2+ biosorption, and they can accordingly be used for wastewater treatment.

PROM is one of the common complications of perinatal period, which seriously threatens the mother and newborn. The purpose of this study was to identify the role of NLRC4 inflammasomes in this process and their underlying mechanisms. We performed high-throughput RNA sequencing of fetal membrane tissue from 3 normal pregnant women and 3 term-premature rupture of fetal membrane (TPROM) patients who met the inclusion criteria, and found that NLRC4 was significantly up-regulated in TPROM patients. An observational study of TPROM patients (PROM group, n = 30) and normal pregnant women (control group, n = 30) was performed at the Xuzhou Maternal and Child Health Hospital affiliated to Xuzhou Medical University from May 2018 to May 2019. The expression of genes involved in inflammasome complex including NLRC1, NLRC3, AIM2, NLRC4, ASC, caspase-1, IL-6, IL-18 and IL-1βwas determined via real-time PCR, immunohistochemistry and immunofluorescence. Measurement of NLRC4 level in serum was conducted by ELISA assay. The results showed that the NLRC4, ASC, caspase-1, IL-1β and IL-18 levels in fetal membrane, placental tissues and maternal serum were markedly higher in the PROM group than that in the control group. In conclusion, NLRC4 is a markedly up-regulated gene in TPROM fetal membrane tissue, suggesting that NLRC4 is involved in the occurrence and development of TPROM; NLRC4 levels in maternal blood serum are closely related to TPROM and have the potential to assist doctors in predicting and diagnosing PROM.

INTRODUCTION:Hepatitis B is a serious public health problem across sub-Saharan Africa. Sierra Leone has no national hepatitis B strategy plan or high quality estimates of prevalence. Healthcare workers are perceived as an at-risk group for hepatitis B. We assessed the prevalence of hepatitis B among healthcare workers at two hospital sites in Freetown, Sierra Leone. METHODS:In October 2017, healthcare workers were offered voluntary testing for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), hepatitis B e antigen (HBeAg) and hepatitis B e antibody (anti-HBe) using rapid lateral flow assay for all samples, followed by Enzyme Immunosorbent Assay to confirm positive results. Participants completed a questionnaire about knowledge, attitudes and practices concerning hepatitis B. HBsAg positive participants were invited to a clinic for further assessment. RESULTS:Overall, 447 participants were tested for hepatitis B. Most (90.6%, 405/447) participants were nurses, 72.3% (323/447) were female and 71.6% (320/447) were 30 years or older. The prevalence of chronic hepatitis B (HBsAg positivity) was 8.7% (39 / 447, 95% CI 6.3-11.7%). There was no significant difference in prevalence by sex, age group, site of work or type of job. None of the 66.7% (26 / 39) of participants with chronic hepatitis B who attended the clinic met the 2015 WHO criteria to start treatment for hepatitis B on the basis of cirrhosis. Most participants (96.9% 432 / 446) stated that they were worried about their risk of hepatitis B at work. CONCLUSIONS:Hepatitis B is highly prevalent among healthcare workers in Sierra Leone. It is unclear whether this reflects high community prevalence or is due to occupational risk. No participants with chronic hepatitis B needed to start treatment. In order to achieve the WHO target of elimination of viral hepatitis by 2030, introduction of birth dose vaccine for infants and catch-up vaccines for healthcare workers and healthcare students, together with a national hepatitis B screen and treat programme is advisable for Sierra Leone.

LRRC55 (leucine-rich repeat-containing protein 55) protein is an auxiliary γ subunit of BK (Big conductance potassium channel) channels, which leftward shifts GVs of BK channels around 50 mV in the absence of cytosolic Ca2+. LRRC55 protein is also the only γ subunit of BK channels that is expressed in mammalian nervous system. However, the expression pattern of LRRC55 gene in adult mammalian brain remains elusive. In this study, we investigated the distribution of LRRC55 mRNA in the adult mouse brain by using in situ hybridization. We found that LRRC55 mRNA is richly expressed in the adult mouse medial habenula nucleus (MHb), cerebellum and pons. However, the potential role of LRRC55 in MHb and cerebellum could be different based on the function of BK channels in these brain regions.

[This corrects the article DOI: 10.1371/journal.pone.0191749.].

Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson's Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.

Androgen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.Blood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.Of 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.CTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.

Independent component analysis (ICA) is widely used in the field of functional neuroimaging to decompose data into spatio-temporal patterns of co-activation. In particular, ICA has found wide usage in the analysis of resting state fMRI (rs-fMRI) data. Recently, a number of large-scale data sets have become publicly available that consist of rs-fMRI scans from thousands of subjects. As a result, efficient ICA algorithms that scale well to the increased number of subjects are required. To address this problem, we propose a two-stage likelihood-based algorithm for performing group ICA, which we denote Parallel Group Independent Component Analysis (PGICA). By utilizing the sequential nature of the algorithm and parallel computing techniques, we are able to efficiently analyze data sets from large numbers of subjects. We illustrate the efficacy of PGICA, which has been implemented in R and is freely available through the Comprehensive R Archive Network, through simulation studies and application to rs-fMRI data from two large multi-subject data sets, consisting of 301 and 779 subjects respectively.

Prediction of protein-protein interaction (PPI) remains a central task in systems biology. With more PPIs identified, forming PPI networks, it has become feasible and also imperative to study PPIs at the network level, such as evolutionary analysis of the networks, for better understanding of PPI networks and for more accurate prediction of pairwise PPIs by leveraging the information gained at the network level. In this work we developed a novel method that enables us to incorporate evolutionary information into geometric space to improve PPI prediction, which in turn can be used to select and evaluate various evolutionary models. The method is tested with cross-validation using human PPI network and yeast PPI network data. The results show that the accuracy of PPI prediction measured by ROC score is increased by up to 14.6%, as compared to a baseline without using evolutionary information. The results also indicate that our modified evolutionary model DANEOsf-combining a gene duplication/neofunctionalization model and scale-free model-has a better fitness and prediction efficacy for these two PPI networks. The improved PPI prediction performance may suggest that our DANEOsf evolutionary model can uncover the underlying evolutionary mechanism for these two PPI networks better than other tested models. Consequently, of particular importance is that our method offers an effective way to select evolutionary models that best capture the underlying evolutionary mechanisms, evaluating the fitness of evolutionary models from the perspective of PPI prediction on real PPI networks.

The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/μL defined as "immunologic responders" and 11 HIV+ subjects with CD4+ T cells below 350 cells/μL defined as "immunologic non-responders". We analyzed NK cell number, subset, and activation by expression of CD107a and NKG2D and co-expression of CD38 and HLA-DR. NK cell-mediated cytotoxicity against uninfected CD4+ T cells was tested in vitro. We found that NK cell absolute number, percentage of NK cells, and percentage of NK cell subsets were similar in the three study groups. The increased NK cell activation was found predominantly in CD56dimCD16+ subset of immunologic non-responders but not immunologic responders compared to healthy controls. The activation of NK cells was inversely correlated with the peripheral CD4+ T cell count in HIV+ subjects, even after controlling for chronic T cell activation, sex, and age, potential contributors for CD4+ T cell counts in HIV disease. Interestingly, NK cells from immunologic non-responders mediated cytotoxicity against uninfected CD4+ T cells ex vivo. NK cells may play a role in blunted CD4+ T cell recovery in ART-treated HIV disease.

China accounts for almost half of the total number of liver cancer cases and deaths worldwide, and hepatocellular carcinoma (HCC) is the most primary liver cancer. Snail family transcriptional repressor 2 (SNAI2) is known as an epithelial to mesenchymal transition-inducing transcription factor that drives neoplastic epithelial cells into mesenchymal phenotype. However, the roles of endogenous SNAI2 remain controversial in different types of malignant tumors. Herein, we surprisingly identify that anchorage-independent growth, including the formation of tumor sphere and soft agar colony, is significantly increased when SNAI2 expression is inhibited by shRNAs in HCC cells. Suppression of SNAI2 suffices to up-regulate several cancer stem genes. Although unrelated to the metastatic ability, SNAI2 inhibition does increase the efflux of Hoechst 33342 and enhance multidrug resistance in vitro and in vivo. In agreement with this data, we demonstrate for the first time that decreasing SNAI2 level can transcriptionally upregulate several ATP binding cassette (ABC) transporter genes such as ABCB1. Moreover, ABC transporters' inhibitor verapamil can rescue the multidrug resistance induced by SNAI2 inhibition. Our results implicate that SNAI2 behaves as a tumor suppressor by inhibiting multidrug resistance via suppressing ABC transporter genes in HCC cells.

Accelerated fibrosis in patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) has been a major cause of mortality in the highly active anti-retroviral therapy (HAART) era. However, the role of co-infection in accelerating the progression of liver fibrosis, particularly with regard to the effects of co-infection on hepatic stellate cells (HSCs), remains unclear. We hypothesized that HIV and HCV induce liver fibrosis synergistically by altering the regulation of epimorphin production, and thereby indirectly alter HSC function. Here, we examined the effects of epimorphin on HSC proliferation and invasion, and the changes in fibrogenesis-related gene activity in HSCs (LX2) in the presence of inactivated CXCR4-tropic HIV and HCV (JFH1). The combination of HIV and HCV significantly increased epimorphin expression, which increased the proliferation and invasion capabilities of HSCs. Epimorphin also induced the expression of profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP1) in an extracellular signal-regulated kinase (ERK)-dependent manner. These data indicated that the effects of HIV/HCV co-infection on hepatic fibrosis might be mediated in part by EPM. Strategies to limit the expression of EPM might represent a novel therapeutic approach to prevent the progression of hepatic fibrosis during HIV/HCV co-infection.

The peripheral nervous system may play an important role in normal bone maintenance and remodeling. Substance P (SP) is a neuropeptide associated with bone loss and formation that may mediate the effects of the nervous system. The purpose of this study is to determine if treadmill running combined with electro-acupuncture at Jiaji acupoints (Jiaji-EA) affects tibial bone mass and SP expression in rabbits with sciatic nerve injury. Twenty-four juvenile male New Zealand white rabbits were randomly assigned to one of 4 groups: sham injury control (sham), sciatic never crush control (SNCr), treadmill running (treadmill), and Jiaji-EA combined with treadmill running (ET group). The SNCr, treadmill, and ET groups all had an induced sciatic never crush injury of approximately 2mm. Control groups received no intervention; the treadmill and ET groups were trained by treadmill; the ET group also received Jiaji-EA. After the 4 weeks of treatment, toe-spreading index (TSI), BMD, bone strength, and SP expression in the tibia were significantly lower in the nerve injury groups (SNCr, treadmill, and ET) compared to the sham groups (p

RNA junctions are important structural elements of RNA molecules. They are formed when three or more helices come together in three-dimensional space. Recent studies have focused on the annotation and prediction of coaxial helical stacking (CHS) motifs within junctions. Here we exploit such predictions to develop an efficient alignment tool to handle RNA secondary structures with CHS motifs. Specifically, we build upon our Junction-Explorer software for predicting coaxial stacking and RNAJAG for modelling junction topologies as tree graphs to incorporate constrained tree matching and dynamic programming algorithms into a new method, called CHSalign, for aligning the secondary structures of RNA molecules containing CHS motifs. Thus, CHSalign is intended to be an efficient alignment tool for RNAs containing similar junctions. Experimental results based on thousands of alignments demonstrate that CHSalign can align two RNA secondary structures containing CHS motifs more accurately than other RNA secondary structure alignment tools. CHSalign yields a high score when aligning two RNA secondary structures with similar CHS motifs or helical arrangement patterns, and a low score otherwise. This new method has been implemented in a web server, and the program is also made freely available, at http://bioinformatics.njit.edu/CHSalign/.

The first genome-wide association study for coronary artery disease (CAD) in the Han Chinese population, we reported recently, had identified rs6903956 in gene ADTRP on chromosome 6p24.1 as a novel susceptibility locus for CAD. The risk allele of rs6903956 was associated with decreased mRNA expression of ADTRP. To further study the correlation of ADTRP expression and CAD, in this study we evaluated the associations of eight common variants in the expression-regulating regions of ADTRP with CAD in the Southern Han Chinese population. Rs169790 in 3'UTR, rs2076189 in 5'UTR, four SNPs (rs2076188, rs7753407, rs11966356 and rs1018383) in promoter, and two SNPs (rs3734273, rs80355771) in the last intron of ADTRP were genotyped in 1716 CAD patients and 1572 controls. The correlations between these loci and total or early-onset CAD were investigated. None of these loci was discovered to associate with total CAD (P > 0.05). However, with early-onset CAD, significant both allelic and genotypic associations of rs7753407, rs11966356 and rs1018383 were identified, after adjustment for risk factors of age, gender, hypertension, diabetes, lipid profiles and smoking (adjusted P < 0.05). A haplotype AGCG (constructed by rs2076188, rs7753407, rs11966356 and rs1018383) was identified to protect subjects from early-onset CAD (OR = 0.332, 95% CI = 0.105-0.879, adjusted P = 0.010). Real-time quantitative reverse transcription polymerase chain reaction assay showed that the risk alleles of the associated loci were significantly associated with decreased expression of ADTRP mRNA. Moreover, the average level of ADTRP mRNA expression in early-onset CAD cases was significantly lower than that in controls. Our results provide new evidence supporting the association of ADTRP with the pathogenesis of early-onset CAD.

Mitogen-activated protein kinase (MAPK) cascades are critical signaling modules that mediate the transduction of extracellular stimuli into intracellular response. A relatively large number of MAPKKKs have been identified in a variety of plant genomes but only a few of them have been studied for their biological function. In the present study, we identified an Arabidopsis Raf-like MAPKKK gene Raf43 and studied its function in biotic and abiotic stress response using a T-DNA insertion mutant raf43-1 and two Raf43-overexpressing lines Raf43-OE#1 and Raf43-OE#13. Expression of Raf43 was induced by multiple abiotic and biotic stresses including treatments with drought, mannitol and oxidative stress or defense signaling molecule salicylic acid and infection with necrotrophic fungal pathogen Botrytis cinerea. Seed germination and seedling root growth of raf43-1 were significantly inhibited on MS medium containing mannitol, NaCl, H2O2 or methyl viologen (MV) while seed germination and seedling root growth of the Raf43-OE#1 and Raf43-OE#13 lines was similar to wild type Col-0 under the above stress conditions. Soil-grown raf43-1 plants exhibited reduced tolerance to MV, drought and salt stress. Abscisic acid inhibited significantly seed germination and seedling root growth of the raf43-1 line but had no effect on the two Raf43-overexpressing lines. Expression of stress-responsive RD17 and DREB2A genes was significantly down-regulated in raf43-1 plants. However, the raf43-1 and Raf43-overexpressing plants showed similar disease phenotype to the wild type plants after infection with B. cinerea or Pseudomonas syringae pv. tomato DC3000. Our results demonstrate that Raf43, encoding for a Raf-like MAPKKK, is required for tolerance to multiple abiotic stresses in Arabidopsis.

Whole exome sequencing has facilitated the discovery of causal genetic variants associated with human diseases at deep coverage and low cost. In particular, the detection of somatic mutations from tumor/normal pairs has provided insights into the cancer genome. Although there is an abundance of publicly-available software for the detection of germline and somatic variants, concordance is generally limited among variant callers and alignment algorithms. Successful integration of variants detected by multiple methods requires in-depth knowledge of the software, access to high-performance computing resources, and advanced programming techniques. We present ExScalibur, a set of fully automated, highly scalable and modulated pipelines for whole exome data analysis. The suite integrates multiple alignment and variant calling algorithms for the accurate detection of germline and somatic mutations with close to 99% sensitivity and specificity. ExScalibur implements streamlined execution of analytical modules, real-time monitoring of pipeline progress, robust handling of errors and intuitive documentation that allows for increased reproducibility and sharing of results and workflows. It runs on local computers, high-performance computing clusters and cloud environments. In addition, we provide a data analysis report utility to facilitate visualization of the results that offers interactive exploration of quality control files, read alignment and variant calls, assisting downstream customization of potential disease-causing mutations. ExScalibur is open-source and is also available as a public image on Amazon cloud.

Leaves of C4 crops usually have higher radiation, water and nitrogen use efficiencies compared to the C3 species. Engineering C4 traits into C3 crops has been proposed as one of the most promising ways to repeal the biomass yield ceiling. To better understand the function of C4 photosynthesis, and to identify candidate genes that are associated with the C4 pathways, a comparative transcription network analysis was conducted on leaf developmental gradients of three C4 species including maize, green foxtail and sorghum and one C3 species, rice. By combining the methods of gene co-expression and differentially co-expression networks, we identified a total of 128 C4 specific genes. Besides the classic C4 shuttle genes, a new set of genes associated with light reaction, starch and sucrose metabolism, metabolites transportation, as well as transcription regulation, were identified as involved in C4 photosynthesis. These findings will provide important insights into the differential gene regulation between C3 and C4 species, and a good genetic resource for establishing C4 pathways in C3 crops.

Cohesive sediment deposits in the Three Gorges Reservoir, China, were used to investigate physical and geochemical properties, biofilm mass, and erosion and deposition characteristics. Biofilm cultivation was performed in a recirculating flume for three different periods (5, 10 and 15 days) under ambient temperature and with sufficient nutrients supply. Three groups of size-fractionated sediment were sequentially used, including 0-0.02 mm, 0.02-0.05 mm and 0.05-0.10 mm. Desired conditions for erosion and deposition were designed by managing high bed shear stress at the narrow part of upstream flume and low shear stress at the wide part of downstream flume. Biostabilization and transport characteristics of the biofilm coated sediment (bio-sediment) were strongly influenced by the cultivation period, and the results were compared with clean sediment. The bio-sediment was more resistant to erosion, and the mean shear stress was increased by factors of 2.65, 2.73 and 5.01 for sediment with 5, 10 and 15 days of biofilm growth compared with clean sediment, resulting in less sediment being eroded from the bed. Simultaneously, the settling velocity was smaller for bio-sediment due to higher organic content and porosity (i.e., lower density). Additionally, there was a smaller probability of deposition for sediment with a longer cultivation period after erosion, resulting in more retention time in aquatic systems. These results will benefit water management in natural rivers.

Warming-induced drought has widely affected forest dynamics in most places of the northern hemisphere. In this study, we assessed how climate warming has affected Picea crassifolia (Qinghai spruce) forests using tree growth-climate relationships and the normalized difference vegetation index (NDVI) along the Qilian Mountains, northeastern Tibet Plateau (the main range of Picea crassifolia). Based on the analysis on trees radial growth data from the upper tree line and the regional NDVI data, we identified a pervasive growth decline in recent decades, most likely caused by warming-induced droughts. The drought stress on Picea crassifolia radial growth were expanding from northeast to southwest and the favorable moisture conditions for tree growth were retreating along the identical direction in the study area over the last half century. Compared to the historical drought stress on tree radial growth in the 1920s, recent warming-induced droughts display a longer-lasting stress with a broader spatial distribution on regional forest growth. If the recent warming continues without the effective moisture increasing, then a notable challenge is developed for Picea crassifolia in the Qilian Mountains. Elaborate forest management is necessary to counteract the future risk of climate change effects in this region.

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS), the most common AIDS-related malignancy. KSHV vIL-6 promotes KS development, but the exact mechanisms remain unclear. Here, we reported that KSHV vIL-6 enhanced the expression of DNA methyltransferase 1 (DNMT1) in endothelial cells,increased the global genomic DNA methylation, and promoted cell proliferation and migration. And this effect could be blocked by the DNA methyltransferase inhibitor, 5-azadeoxycytidine. We also showed that vIL-6 induced up-regulation of DNMT1 was dependent on STAT3 activation. Therefore, the present study suggests that vIL-6 plays a role in KS tumorigenesis partly by activating DNMT1 and inducing aberrant DNA methylation, and it might be a potential target for KS therapy.

We previously reported that bupivacaine induces reactive oxygen species (ROS) generation, p38 mitogen-activated protein kinase (MAPK) activation and nuclear factor-kappa B activation, resulting in an increase in expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. However, the identity of signaling upstream of p38 MAPK pathways to WDR35 expression remains unclear. It has been shown that AMP-activated protein kinase (AMPK) can activate p38 MAPK through diverse mechanisms. In addition, several kinases acting upstream of AMPK have been identified including Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). Recent studies reported that AMPK may be involved in bupivacaine-induced cytotoxicity in Schwann cells and in human neuroblastoma SH-SY5Y cells. The present study was undertaken to test whether CaMKK and AMPK are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Our results showed that bupivacaine induced activation of AMPK and p38 MAPK in Neuro2a cells. The AMPK inhibitors, compound C and iodotubercidin, attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. Treatment with the CaMKK inhibitor STO-609 also attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. These results suggest that bupivacaine activates AMPK and p38 MAPK via CaMKK in Neuro2a cells, and that the CaMKK/AMPK/p38 MAPK pathway is involved in regulating WDR35 expression.

The family of WD repeat proteins comprises a large number of proteins and is involved in a wide variety of cellular processes such as signal transduction, cell growth, proliferation, and apoptosis. Bupivacaine is a sodium channel blocker administered for local infiltration, nerve block, epidural, and intrathecal anesthesia. Recently, we reported that bupivacaine induces reactive oxygen species (ROS) generation and p38 mitogen-activated protein kinase (MAPK) activation, resulting in an increase in the expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. It has been shown that ROS activate MAPK through phosphorylation, followed by activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). The present study was undertaken to test whether NF-κB and c-Jun/AP-1 are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Bupivacaine activated both NF-κB and c-Jun in Neuro2a cells. APDC, an NF-κB inhibitor, attenuated the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. GW9662, a selective peroxisome proliferator-activated receptor-γ antagonist, enhanced the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. In contrast, c-Jun siRNA did not inhibit the bupivacaine-induced increase in WDR35 mRNA expression. These results indicate that bupivacaine induces the activation of transcription factors NF-κB and c-Jun/AP-1 in Neuro2a cells, while activation of NF-κB is involved in bupivacaine-induced increases in WDR35 expression.

BACKGROUND:After the 2003 publication of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, there was a 5-10% increase in patients initiating antihypertensive medication with a thiazide-type diuretic, but most patients still did not initiate treatment with this class. There are few contemporary published data on antihypertensive medication classes filled by patients initiating treatment. METHODS AND FINDINGS:We used the 5% random Medicare sample to study the initiation of antihypertensive medication between 2007 and 2010. Initiation was defined by the first antihypertensive medication fill preceded by 365 days with no antihypertensive medication fills. We restricted our analysis to beneficiaries ≥ 65 years who had two or more outpatient visits with a hypertension diagnosis and full Medicare fee-for-service coverage for the 365 days prior to initiation of antihypertensive medication. Between 2007 and 2010, 32,142 beneficiaries in the 5% Medicare sample initiated antihypertensive medication. Initiation with a thiazide-type diuretic decreased from 19.2% in 2007 to 17.9% in 2010. No other changes in medication classes initiated occurred over this period. Among those initiating antihypertensive medication in 2010, 31.3% filled angiotensin-converting enzyme inhibitors (ACE-Is), 26.9% filled beta blockers, 17.2% filled calcium channel blockers, and 14.4% filled angiotensin receptor blockers (ARBs). Initiation with >1 antihypertensive medication class decreased from 25.6% in 2007 to 24.1% in 2010. Patients initiated >1 antihypertensive medication class most commonly with a thiazide-type diuretic and either an ACE-I or ARB. CONCLUSION:These results suggest that JNC 7 had a limited long-term impact on the choice of antihypertensive medication class and provide baseline data prior to the publication of the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).

The vulnerable Chinese cobra (Naja atra) ranges from southeastern China south of the Yangtze River to northern Vietnam and Laos. Large mountain ranges and water bodies may influence the pattern of genetic diversity of this species. We sequenced the mitochondrial DNA control region (1029 bp) using 285 individuals collected from 23 localities across the species' range and obtained 18 sequences unique to Taiwan from GenBank for phylogenetic and population analysis. Two distinct clades were identified, one including haplotypes from the two westernmost localities (Hekou and Miyi) and the other including haplotypes from all sampling sites except Miyi. A strong population structure was found (Φst = 0.76, P

BACKGROUND: The effect of neoadjuvant chemotherapy (NAC) on Gastric carcinoma (GC) has been extensively studied, while its survival and surgical benefits remain controversial. This study aims to perform a meta-analysis of high-quality randomized controlled trials (RCTs), comparing efficacy, safety and other outcomes of NAC followed by surgery with surgery alone (SA) for GC. METHODS: We systematically searched databases of MEDLINE, EMBASE, The Cochrane Library and Springer for RCTs comparing NAC with SA when treating GC. Reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases were also searched. Primary outcomes were 3-year and 5-year survival rates, survival time, and total and perioperative mortalities. Secondary outcomes included down-staging effects, R0 resection rate, and postoperative complications. Meta-analysis was conducted where possible comparing items using relative risks (RRs) and weighted mean differences (WMDs) according to type of data. NAC-related objective response, safety and toxicity were also specifically analyzed. RESULTS: A total of 9 RCTs comparing NAC (n = 511) with SA (n = 545) published from 1995 to 2010 were identified. SA tended to be accompanied with higher overall mortality rate than NAC (46.03% vs 40.61%, RR: 0.83, 95% CI: 0.65-1.06, P = 0.14). Significantly, higher incidence of cases without regional lymph node metastasis observed upon resection were achieved among patients receiving NAC than those undergoing SA (25.68% vs 16.95%, RR: 1.92, 95% CI: 1.20-3.06, P = 0.006). All other parameters were comparable. Of the evaluable patients, 43.0% demonstrated either complete or partial response. The comprehensive NAC-related side-effect rate was 18.2% among patients available for safety assessment. CONCLUSIONS: NAC contributes to lowering nodal stages, and potentially reduces overall mortality. Response rate may be an important influential factor impacting advantages, with chemotherapy-related adverse effects as a drawback. This level 1a evidence doesn't support NAC to outweigh SA in terms of survival and surgical benefits when dealing with GC.

Biotic and abiotic stresses are major unfavorable factors that affect crop productivity worldwide. NAC proteins comprise a large family of transcription factors that play important roles in plant growth and development as well as in responses to biotic and abiotic stresses. In a virus-induced gene silencing-based screening to identify genes that are involved in defense response against Botrytis cinerea, we identified a tomato NAC gene SlSRN1 (Solanum lycopersicum Stress-related NAC1). SlSRN1 is a plasma membrane-localized protein with transactivation activity in yeast. Expression of SlSRN1 was significantly induced by infection with B. cinerea or Pseudomonas syringae pv. tomato (Pst) DC3000, leading to 6-8 folds higher than that in the mock-inoculated plants. Expression of SlSRN1 was also induced by salicylic acid, jasmonic acid and 1-amino cyclopropane-1-carboxylic acid and by drought stress. Silencing of SlSRN1 resulted in increased severity of diseases caused by B. cinerea and Pst DC3000. However, silencing of SlSRN1 resulted in increased tolerance against oxidative and drought stresses. Furthermore, silencing of SlSRN1 accelerated accumulation of reactive oxygen species but attenuated expression of defense genes after infection by B. cinerea. Our results demonstrate that SlSRN1 is a positive regulator of defense response against B. cinerea and Pst DC3000 but is a negative regulator for oxidative and drought stress response in tomato.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by abnormal remodeling of small, peripheral pulmonary arteries. Germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for developing PAH. At present, the correlation between the BMPR2 mutation and the patient's prognosis remains controversial despite several investigations. In this study, we explored the functional effects of four BMPR2 mutations to dissect the functional significance of the BMPR2 gene defect. Cellular immunofluorescence assay of four mutants (Tyr67Cys, Thr268fs, Ser863Asn, and Gln433X) revealed that the BMPR2 protein containing Thr268fs, Ser863Asn, or Gln433X exhibited abnormal subcellular localization. The BrdU incorporation and TUNEL assay suggested that any of the BMPR2 mutations Thr268fs, Ser863Asn, or Gln433X could improve endothelial cell apoptosis and decrease cell proliferation. All of the four mutants could inhibit nitric oxide (NO) synthesis in HLMVE cells, and ET-1 levels increased in the cells transfected with mutant Ser863Asn. Our results will improve the understanding of the genotype-phenotype correlations and mechanisms associated with BMPR2 mutations.

Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract and loss of ICC is associated with many GI motility disorders. Previous studies have shown that ICC have the capacity to regenerate or restore, and several growth factors are critical to their growth, maintenance or regeneration. The present study aimed to investigate the roles of interleukin-9 (IL-9) in the growth, maintenance and pacemaker functions of cultured ICC. Here, we report that IL-9 promotes proliferation of ICC, and culturing ICC with IL-9 enhances cholecystokinin-8-induced Ca²⁺ transients, which is probably caused by facilitating maintenance of ICC functions under culture condition. We also show co-localizations of cholecystokinin-1 receptor and IL-9 receptor with c-kit by double-immunohistochemical labeling. In conclusion, IL-9 can promote ICC growth and help maintain ICC functions; IL-9 probably performs its functions via IL-9 receptors on ICC.

Erythromycins (Ers) are clinically potent macrolide antibiotics in treating pathogenic bacterial infections. Microorganisms capable of producing Ers, represented by Saccharopolyspora erythraea, are mainly soil-dwelling actinomycetes. So far, Actinopolyspora erythraea YIM90600, a halophilic actinomycete isolated from Baicheng salt field, is the only known Er-producing extremophile. In this study, we have reported the draft genome sequence of Ac. erythraea YIM90600, genome mining of which has revealed a new Er biosynthetic gene cluster encoding several novel Er metabolites. This Er gene cluster shares high identity and similarity with the one of Sa. erythraea NRRL2338, except for two absent genes, eryBI and eryG. By correlating genotype and chemotype, the biosynthetic pathways of 3'-demethyl-erythromycin C, erythronolide H (EH) and erythronolide I have been proposed. The formation of EH is supposed to be sequentially biosynthesized via C-6/C-18 epoxidation and C-14 hydroxylation from 6-deoxyerythronolide B. Although an in vitro enzymatic activity assay has provided limited evidence for the involvement of the cytochrome P450 oxidase EryFAc (derived from Ac. erythraea YIM90600) in the catalysis of a two-step oxidation, resulting in an epoxy moiety, the attempt to construct an EH-producing Sa. erythraea mutant via gene complementation was not successful. Characterization of EryKAc (derived from Ac. erythraea YIM90600) in vitro has confirmed its unique role as a C-12 hydroxylase, rather than a C-14 hydroxylase of the erythronolide. Genomic characterization of the halophile Ac. erythraea YIM90600 will assist us to explore the great potential of extremophiles, and promote the understanding of EH formation, which will shed new insights into the biosynthesis of Er metabolites.