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Here, we investigate the role of SmERF73, a group VII ETHYLENE RESPONSE FACTOR stress response transcription factor, in the regulation of post-modification of the skeleton precursors of diterpene tanshinones in Salvia miltiorrhiza. Most genes found to be involved in tanshinone biosynthesis are located on chromosome 6, and five of these genes comprise a large gene cluster in S. miltiorrhiza. We found that SmERF73 overexpression in S. miltiorrhiza coordinately up-regulated the transcription of seven tanshinone biosynthetic genes, four of which were located in the tanshinone gene cluster, consequently increasing tanshinone accumulation, while SmERF73 silencing reduced corresponding gene transcription and tanshinone accumulation. SmERF73 recognizes GCC-box promoter elements of four tanshinone-associated genes (DXR1, CPS1, KSL1 and CYP76AH3) and activates their expression. Moreover, SmERF73 and its targets were up-regulated by stress elicitors; SmERF73 appears to be at least partly mediated by the jasmonic acid (JA) signaling pathway via interaction with SmJAZ3. SmERF73 coordinately regulates tanshinone biosynthetic gene expression, suggesting a potential link between tanshinone production and plant stress responses.

Objective Systemic sclerosis (SSc) is a rare debilitating autoimmune disease of the connective tissue. This study aimed to assess the recent prevalence and incidence of SSc across the world. Methods Using a systematic search strategy, PubMed/MEDLINE and EMBASE were searched to identify relevant studies published between 2006 and 2016. Two reviewers independently evaluated studies for inclusion based on inclusion/exclusion criteria and performed data extraction. The review was conducted and reported following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The pooled prevalence of SSc was calculated by meta-analysis using a random-effects model. Results There were 1364 references retrieved using the initial searching strategy, and 20 epidemiological publications were selected for data extraction. The identified studies reported prevalence ranging from 3.8 per 100 000 in Taiwan to 50 per 100 000 in the USA. The prevalence was 23 per 100 000 (95% CI: 16-29 per 100 000; 18 studies) in a pooled sample of 11 574 individuals. Incidence rate of SSc ranges from 0.77 per 100 000 person-years in the Netherlands to 5.6 per 100 000 person-years in the USA. SSc predominates in females with higher prevalence and incidence rates. It is important to note that different methodologies were used to derive these numbers so comparisons were made with caution. Conclusion This review provides an assessment of the current estimates of disease prevalence and incidence of SSc. The epidemiological burdens of SSc vary among different regions of the world. The epidemiological data need to be interpreted with caution considering the methodological differences in deriving these estimates.

Purpose The SARS‐CoV‐2 RNA has been detected in tears and conjunctival samples from infected individuals. Conjunctivitis is also reported in a small number of cases. We evaluated ocular symptoms and ocular tropism of SARS‐CoV‐2 in a group of patients with COVID‐19. Method Fifty‐six patients infected with SARS‐CoV‐2 were recruited as subjects. Relevant medical histories were obtained from the electronic medical record system. Ocular history and ocular symptoms data were obtained by communicating directly with the subjects. The Ocular Surface Disease Index (OSDI) and Salisbury Eye Evaluation Questionnaire (SEEQ) were used to assess the anterior ocular surface condition before and after the onset of disease. Results Patients classified as severe COVID‐19 cases were more likely to have hypertension compared to mild cases (p = 0.035). Of the 56 subjects, thirteen patients (23%) were infected in Wuhan, 32 patients (57%) were community‐infected, 10 patients (18%) were unknown origin, 1 (2%) was a physician likely infected by a confirmed patient. Three patients wore face mask with precaution when contacting the confirmed patients. Fifteen (27%) had aggravated ocular symptoms, of which 6 (11%) had prodromal ocular symptoms before disease onset. The differences in mean scores of OSDI questionnaire and SEEQ between before and after onset of COVID‐19 were all significant (p

Objective This study aimed to assess the presence of novel coronavirus in tears and conjunctival secretions of SARS-CoV-2-infected patients. Methods A prospective interventional case series study was performed, and 30 confirmed novel coronavirus pneumonia (NCP) patients were selected at the First Affiliated Hospital of Zhejiang University from 26 January 2020 to 9 February 2020. At an interval of 2 to 3 days, tear and conjunctival secretions were collected twice with disposable sampling swabs for reverse-transcription polymerase chain reaction (RT-PCR) assay. Results Twenty-one common-type and nine severe-type NCP patients were enrolled. Two samples of tear and conjunctival secretions were obtained from the only one patient with conjunctivitis yielded positive RT-PCR results. Fifty-eight samples from other patents were all negative. Conclusion We speculate that SARS-CoV-2 may be detected in the tears and conjunctival secretions in NCP patients with conjunctivitis.

Picroside II (P‐II), one of the main active components of scrophularia extract, which have anti‐oxidative, anti‐inflammatory effects, but its effect on hyperhomocysteinemia (HHcy) induced endothelial injury remains to be determined. Here, we test whether P‐II protects HHcy‐induced endothelial dysfunction against oxidative stress, inflammation and cell apoptosis. In vitro study using HUVECs, and in hyperhomocysteinemia mouse models, we found that HHcy decreased endothelial SIRT1 expression and increased LOX‐1 expression, subsequently causing reactive oxygen species generation, up‐regulation of NADPH oxidase activity and NF‐κB activation, thereby promoting pro‐inflammatory response and cell apoptosis. Blockade of Sirt1 with Ex527 or siRNASIRT1 increased LOX‐1 expression, whereas overexpression of SIRT1 decreased LOX‐1 expression markedly. P‐II treatment significantly increased SIRT1 expression and reduced LOX‐1 expression, and protected against endothelial cells from Hcy‐induced oxidative injury, inflammation and apoptosis. However, blockade of SIRT1 or overexpression of LOX‐1 attenuated the therapeutic effects of P‐II. In conclusion, our results suggest that P‐II prevents the Hcy induced endothelial damage probably through regulating the SIRT1/LOX‐1 signaling pathway.

The conjunctival mucosa is directly exposed to infectious droplets expelled by patients during close contact and fomites when the eye is touched by contaminated hands.2, 3 More over, the mucosa of the conjunctiva and upper respiratory tract is connected by nasolacrimal duct, and share the same entry receptor of SARS‐CoV‐2, angiotensin‐converting enzyme 2 (ACE2), on host cell membranes.2, 3 Hence, it is reasonable to postulate that the conjunctiva may be easily involved in SARS‐CoV‐2 infection, and may even act as a route of transmission during SARS‐CoV‐2 infection. This article is protected by copyright. All rights reserved.

Recurrent event data are quite common in biomedical and epidemiological studies. A significant portion of these data also contain additional longitudinal information on surrogate markers. Previous studies have shown that popular methods using a Cox model with longitudinal outcomes as time-dependent covariates may lead to biased results, especially when longitudinal outcomes are measured with error. Hence, it is important to incorporate longitudinal information into the analysis properly. To achieve this, we model the correlation between longitudinal and recurrent event processes using latent random effect terms. We then propose a two-stage conditional estimating equation approach to model the rate function of recurrent event process conditioned on the observed longitudinal information. The performance of our proposed approach is evaluated through simulation. We also apply the approach to analyze cocaine addiction data collected by the University of Connecticut Health Center. The data include recurrent event information on cocaine relapse and longitudinal cocaine craving scores. Copyright © 2016 John Wiley & Sons, Ltd.

Cytochromes P450 (CYPs) play a key role in generating the structural diversity of terpenoids, the largest group of plant natural products. However, functional characterization of CYPs has been challenging because of the expansive families found in plant genomes, diverse reactivity and inaccessibility of their substrates and products. Here we present the characterization of two CYPs, CYP76AH3 and CYP76AK1, which act sequentially to form a bifurcating pathway for the biosynthesis of tanshinones, the oxygenated diterpenoids from the Chinese medicinal plant Danshen (Salvia miltiorrhiza). These CYPs had similar transcription profiles to that of the known gene responsible for tanshinone production in elicited Danshen hairy roots. Biochemical and RNA interference studies demonstrated that both CYPs are promiscuous. CYP76AH3 oxidizes ferruginol at two different carbon centers, and CYP76AK1 hydroxylates C-20 of two of the resulting intermediates. Together, these convert ferruginol into 11,20-dihydroxy ferruginol and 11,20-dihydroxy sugiol en route to tanshinones. Moreover, we demonstrated the utility of these CYPs by engineering yeast for heterologous production of six oxygenated diterpenoids, which in turn enabled structural characterization of three novel compounds produced by CYP-mediated oxidation. Our results highlight the incorporation of multiple CYPs into diterpenoid metabolic engineering, and a continuing trend of CYP promiscuity generating complex networks in terpenoid biosynthesis.

Summary Hypoferraemia (i.e. iron deficiency) was initially reported among obese individuals several decades ago; however, whether obesity and iron deficiency are correlated remains unclear. Here, we evaluated the putative association between obesity and iron deficiency by assessing the concentration of haematological iron markers and the risks associated with iron deficiency in both obese (including overweight) subjects and non-overweight participants. We performed a systematic search in the databases PubMed and Embase for relevant research articles published through December 2014. A total of 26 cross-sectional and case–control studies were analysed, comprising 13,393 overweight/obese individuals and 26,621 non-overweight participants. Weighted or standardized mean differences of blood iron markers and odds ratio (OR) of iron deficiency were compared between the overweight/obese participants and the non-overweight participants using a random-effects model. Compared with the non-overweight participants, the overweight/obese participants had lower serum iron concentrations (weighted mean difference [WMD]: −8.37 μg dL−1; 95% confidence interval [CI]: −11.38 to −5.36 μg dL−1) and lower transferrin saturation percentages (WMD: 2.34%, 95% CI: −3.29% to −1.40%). Consistent with this finding, the overweight/obese participants had a significantly increased risk of iron deficiency (OR: 1.31; 95% CI: 1.01–1.68). Moreover, subgroup analyses revealed that the method used to diagnose iron deficiency can have a critical effect on the results of the association test; specifically, we found a significant correlation between iron deficiency and obesity in studies without a ferritin-based diagnosis, but not in studies that used a ferritin-based diagnosis. Based upon these findings, we concluded that obesity is significantly associated with iron deficiency, and we recommend early monitoring and treatment of iron deficiency in overweight and obese individuals. Future longitudinal studies will help to test whether causal relationship exists between obesity and iron deficiency.

Since its discovery, diverse functions have been attributed to the G0/G1 switch gene 2 (G0S2), from lipid metabolism to control of cell proliferation. Our group showed for the first time that G0S2 promotes quiescence in hematopoietic stem cells by interacting with and retaining nucleolin around the nucleus. Herein, we report the role of G0S2 in the differentiation and function of CD8(+) T cells examined in mice with an embryonic deletion of the G0s2 gene. G0S2 expression in naïve CD8(+) T cells decreased immediately after T-cell receptor activation downstream of the mitogen-activated protein kinase, calcium/calmodulin, phosphatidylinositol 3'-kinase and mammalian target of rapamycin pathways. Surprisingly, G0S2-null naïve CD8(+) T cells displayed increased basal and spare respiratory capacity that was not associated with increased mitochondrial biogenesis but with increased phosphorylation of AMP-activated protein kinase α. Naïve CD8(+) T cells showed increased proliferation in response to in vitro activation and in vivo lymphopenia; however, naïve CD8(+) T cells expressing the OT-1 transgene exhibited normal differentiation of naïve cells to effector and memory CD8(+) T cells upon infection with Listeria monocytogenes in a wild-type or a G0s2-null environment, with increased circulating levels of free fatty acids. Collectively, our results suggest that G0S2 inhibits energy production by oxidative phosphorylation to fine-tune proliferation in homeostatic conditions.

OBJECTIVE The aim of this study was to evaluate the value of ultrasound scores obtained by conventional ultrasonography and ultrasound elastography in the differentiation of benign and malignant thyroid nodules in Chinese patients. METHODS This study included 297 patients who were referred for surgery for compressive symptoms or suspicion of malignancy. Five hundred and twelve thyroid nodules were examined by ultrasonography. The final diagnosis was based on histological findings. A seven-point ultrasound scoring system based on conventional ultrasonography and a five-point scoring system based on ultrasound elastography were applied independently or in combination. The receiver operating characteristic (ROC) curves were graphed, and the areas under the curves (AUCs) were compared using the χ(2) -test. RESULTS Solid composition, hypo-echoic appearance, an irregular or blurred margin, an aspect ratio ≥1, intranodular blood flow and presence of microcalcifications were significant predictors of malignant thyroid nodules. The AUC (95% CI) was 0·9067 (0·8817-0·9318) for the ultrasound scores based on conventional ultrasonography and 0·9080 (0·8842-0·9317) for the elasticity scores. The combination of these two scoring systems provided good accuracy with an AUC (95% CI) of 0·9415 (0·9223-0·9606), which was significantly higher than that obtained with the conventional ultrasound scores (χ(2) = 36·03, P

The tumor burden (TB) process is postulated to be the primary mechanism through which most anticancer treatments provide benefit. In phase II oncology trials, the biologic effects of a therapeutic agent are often analyzed using conventional endpoints for best response, such as objective response rate and progression-free survival, both of which causes loss of information. On the other hand, graphical methods including spider plot and waterfall plot lack any statistical inference when there is more than one treatment arm. Therefore, longitudinal analysis of TB data is well recognized as a better approach for treatment evaluation. However, longitudinal TB process suffers from informative missingness because of progression or death. We propose to analyze the treatment effect on tumor growth kinetics using a joint modeling framework accounting for the informative missing mechanism. Our approach is illustrated by multisetting simulation studies and an application to a nonsmall-cell lung cancer data set. The proposed analyses can be performed in early-phase clinical trials to better characterize treatment effect and thereby inform decision-making.

The roots of Salvia miltiorrhiza Bge., named Danshen in traditional Chinese medicine, is widely used for the treatment of cardiovascular disorders, also for food auxiliary agent. Rosmarinic acid, salvianolic acid B, dihydrotanshinone, cryptotanshinone, and tanshi- none IIA are all responsible for the pharmacological activity of Danshen, they are important quality evaluation index for Danshen. The quality evaluation of Danshen is mainly concentrated in difference of cultivated regions and years, but the difference in root systems themselves and the cause of the difference were overlook. The growth rings were employed to identified the roots ages in root systems. Then the contents of eight bioactive component in different aged, diameter and tissue of individual roots of the same root system were evaluated using HPLC coupled with an ultraviolet photodiode array detector. The root system of S. miltiorrhiza was a complex root systems composed by different aged and diameter roots, in which the contents of bioactive com- pounds vary greatly from the other. The lipophilic diterpenoid quinones mainly distributed in the bark and increased with the cultivated years. The hydrophilic depsides distributed in all tis- sues, and the contents are relatively high in xylem in 1-year-old roots. It was very important to identify the individual root age of S. miltiorrhiza root system cultivated for several years. In the same root system of S. miltiorrhiza roots with 0.4-cm diameter contain more bioactive com- pounds, which maybe cause by the uneven distribution of bioactive compounds. Microsc. Res. Tech. 76:947-954, 2013. V C 2013 Wiley Periodicals, Inc.

Small-diameter blood vessel substitutes are urgently needed for patients requiring replacements of their coronary and below-the-knee vessels and for better arteriovenous dialysis shunts. Circulatory diseases, especially those arising from atherosclerosis, are the predominant cause of mortality and morbidity in the developed world. Current therapies include the use of autologous vessels or synthetic materials as vessel replacements. The limited availability of healthy vessels for use as bypass grafts and the failure of purely synthetic materials in small-diameter sites necessitate the development of a biological substitute. Tissue engineering is such an approach and has achieved promising results, but reconstruction of a functional vascular tunica media, with circumferentially oriented contractile smooth muscle cells (SMCs) and extracellular matrix, appropriate mechanical properties, and vasoactivity has yet to be demonstrated. This review focuses on strategies to effect the switch of SMC phenotype from synthetic to contractile, which is regarded as crucial for the engineering of a functional vascular media. The synthetic SMC phenotype is desired initially for cell proliferation and tissue remodeling, but the contractile phenotype is then necessary for sufficient vasoactivity and inhibition of neointima formation. The factors governing the switch to a more contractile phenotype with in vitro culture are reviewed.

Ionic hydrogels are attractive for the protection, delivery and controlled release of charged biomacromolecules such as proteins, growth factors or DNA. We have preparted and characterized a series of photocrosslinked anionic hydrogels based on water soluble methacrylated (MA) O-carboxymethylchitosan (OCMCS) and polyethylene glycol (PEG) diacrylate. OCMCS samples with varying degree of substitution of carboxymethyl group ranging from 0.69 to 1.86 were prepared by reacting native chitosan with different amounts of monochloroacetic acid. The OCMCS products demonstrated differences in solubility, zeta potential (-52.7 to -12.8 mV) and thermal decomposition temperature (260 to 283 degrees C). The OCMCS products were then reacted with glycidyl methacrylate to make ultra-violet (UV) crosslinkable OCMCS-MAs which were blended with PEG diacrylate, a photoinitiator and water and successfully photocrosslinked to create OCMCS-MA/PEG hydrogels. Water uptake of the hydrogels varied between 226 % to 358 % and the porous structures of the prepared OCMCS-MA/PEG hydrogels could be modulated by the degree of methacrylation. All the OCMCS-MA/PEG hydrogel substrates similarly supported attachment and proliferation of Smooth Muscle Cells (SMCs). The in vitro biodegradation of these hydrogels, in the presence of SMCs, could be controlled by the degree of methacrylation; weight loss after 9-week was (15+/-1) % and (19+/-2) % using OCMCS 4-MA (12.7 % MA) and OCMCS 1-MA (4.6 % MA), respectively. In addition, the hydrogel based on the most anionic OCMCS 1 showed higher adsorption of basic TGF-beta(1) than similarly modified -agarose, -dextran, and -chondroitin sulfate hydrogels.

Starting from 2-benzylidenebenzofuran-3-ones the synthesis of chiral dihydropyran-fused benzofurans is elaborated.

Stochastic introgression of alien DNA may impose a genomic stress to the recipient genome. Herein, we report that apparent de novo genomic rearrangements in 10 of 13 selected endogenous, low-copy, and potentially active long terminal repeat (LTR) retrotransposons occurred in one or more of three rice lines studied that were introgressed by wild rice (Zizania latifolia Griseb.). For nine retrotransposons in which both the reverse-transcriptase (RT) region and the LTR region were available, largely concordant rearrangements occurred at both regions in five elements and at the RT region only in the remaining four elements. A marked proportion of the genomic changes was shared by two or all three introgression lines that were derived from a single F1 plant. This indicates that most of the genomic changes occurred at early developmental stages of the F1 somatic cells, which then gave rise to germline cells, and, hence, ensured inheritance of the changes to later generations. Possible causes and potential implications of the introgression-induced genomic rearrangements in LTR retrotransposons are discussed in the context of plant genome evolution and breeding. (Managing editor: Li-Hui)

Lycoris longituba is a tulip-like ornamental plant in China. We report on the data mining of L. longituba expressed sequence tags (ESTs) to generate simple sequence repeat (SSRs) markers. Eighteen EST-SSRs were isolated and validated for 32 individuals. These markers will be valuable for studying the genetic structure and diversity of populations for L. longituba.