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Background/aims To determine the association between aspirin use and diabetic retinopathy (DR) among persons with diabetes, in a population-based, cross-sectional study. Methods Subjects with diabetes aged >40 years from the Singapore Epidemiology of Eye Diseases Study were enrolled in this study. Retinal photographs were graded for DR according to the modified Airlie House classification system. Vision threatening diabetic retinopathy (VTDR) was defined as the presence of severe non-proliferative DR, or proliferative DR, or clinically significant macular oedema. The association between aspirin use and the presence of DR or VTDR was assessed using multivariable logistic regression models including age, gender, ethnicity, socioeconomic status, HbA1c, systolic blood pressure, anti-hypertension medicine, total cholesterol, anti-cholesterol medicine, BMI, current smoking status, diabetes duration, history of cardiovascular disease (CVD) and chronic kidney disease (CKD.). Results A total of 2,061 participants with diabetes and complete record of relevant systemic and DR data were included. Of these, 711 (34.5%) had any stage of DR, and among these 177 (8.6%) had VTDR. After adjusting for co-variables listed, the association between aspirin use and VTDR was significant (OR = 1.69, P = 0.019), while the association between aspirin use and any DR was borderline (OR = 1.31, P = 0.063). Aspirin use was not associated with either DR or VTDR after additional adjustment of CVD and CKD. Further stratification by history of CVD or CKD showed no association between aspirin use and DR/VTDR in either subgroup. Conclusion Aspirin use was not significantly associated with DR but might be an indicator of diabetic complications (CVD, CKD) that were co-present with more severe DR type. Future longitudinal studies are warranted to confirm our findings.

Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.

The exact mechanisms of interplay between host and viral factors leading to severe dengue are yet to be fully understood. Even though previous studies have implicated specific genetic differences of Dengue virus (DENV) in clinical severity and virus attenuation, similar studies with large-scale, whole genome screening of monophyletic virus populations are limited. Therefore, in the present study, we compared 89 whole genomes of DENV-2 cosmopolitan clade III isolates obtained from patients diagnosed with dengue fever (DF, n = 58), dengue hemorrhagic fever (DHF, n = 30) and dengue shock syndrome (DSS, n = 1) in Singapore between July 2010 and January 2013, in order to determine the correlation of observed viral genetic differences with clinical outcomes. Our findings showed no significant difference between the number of primary and secondary infections that progressed to DHF and DSS (p>0.05) in our study cohort. Despite being highly homogenous, study isolates possessed 39 amino acid substitutions of which 10 substitutions were fixed in three main groups of virus isolates. None of those substitutions were specifically associated with DHF and DSS. Notably, two evolutionarily unique virus groups possessing C-P43T+NS1-S103T+NS2A-V83I+NS3-R337K+ NS3-I600T+ NS5-P136S and NS2A-T119N mutations were exclusively found in patients with DF, the benign form of DENV infections. Those mutants were significantly associated with mild disease outcome. These observations indicated that disease progression into DHF and DSS within our patient population was more likely to be due to host than virus factors. We hypothesize that selection for potentially less virulent groups of DENV-2 in our study cohort may be an evolutionary adaptation of viral strains to extend their survival in the human-mosquito transmission cycle.

Many studies have explored the social consequences of ethnic essentialism in recent decades. In addition, a few studies have focused on the impact of perceived cultural context on ethnic essentialism. However, it is not clear why perceived cultural context can lead to changes in ethnic essentialism. In the present study, we hypothesized that the cultural anxiety of ethnic minorities may trigger a strong endorsement of and support for a multicultural ideology, thereby affecting beliefs about ethnic groups. To address the issue, 226 Tibetan and 102 Hui college students from Mainland China completed our questionnaires. The results across the two samples showed that (1) cultural anxiety was positively associated with both the endorsement of a multicultural ideology and ethnic essentialism, (2) cultural anxiety and the endorsement of a multicultural ideology positively predicted ethnic essentialism after controlling for demographic variables, and (3) cultural anxiety had both a direct effect on ethnic essentialism and an indirect effect on ethnic essentialism through the endorsement of a multicultural ideology. Our findings suggest that when ethnic minorities experience cultural anxiety, they might endorse a multicultural ideology and adopt essentialism to affirm their ethnic identities.

BACKGROUND: USPIO is a contrast agent for MRI that can generate T2W images with low signal intensities. After subcutaneous or intravenous injection of USPIO, normal lymph node tissues uptake these nano-particles, but tumor cells do not. Thus, tumor metastasis can be detected using this contrast agent. OBJECTIVE: The aim of this study was to access the feasibility of USPIO enhanced MRI for the detection of cervical lymph node metastasis in a pyriform sinus carcinoma animal model and to investigate the ability of USPIO to enhance images of cervical lymph node metastases. METHODS AND FINDINGS: Twenty New Zealand rabbits were randomly divided into tumor and inflammatory groups, and each group contained 10 rabbits. In the inflammatory group, a 0.5 ml egg yolk emulsion was injected into the sub-mandibular muscle of the rabbits to induce an inflammatory reaction in their cervical lymph nodes. In the tumor group, a VX2 tumor tissue suspension was transplanted into the pyriform sinus sub-mucosa of the rabbits using direct laryngoscope. Four weeks after the tumor or egg yolk injection, MRIs were performed before and after USPIO injection to observe the imaging enhancement features of USPIO. After that, a histo-pathological analysis was performed for all rabbits. We found the metastatic lymph nodes had no signal reduced intensity or irregular signal reduced intensity on T2-weighted image by using USPIO enhancement. In the tumor group,the sensitivity and specificity of plain MRI were 57.6% and 60.7%. The corresponding values of USPIO-enhanced MRl were 96.1% and 85.7%. (P

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor because the molecular mechanisms underlying hepatocarcinogenesis are not well understood. In the study, we focused on identifying the role of miRNAs in HCC progression. miRNA microarray was used to analyze the differentially expressed miRNAs, and the results were validated by qPCR. We found that the miR-150-5p expression is down-regulated in HCC tissues compared with pair non-tumor tissues. miR-150-5p expression is also decreased in metastatic cancer tissues compared with pair primary tissues, indicating that miR-150-5p may be involved in HCC metastasis. Functionally, miR-150-5p inhibition significantly promotes hepatoma cell migration and invasion, whereas miR-150-5p overexpression suppresses cancer cell migration and invasion in vitro. The matrix metalloproteinase 14 (MMP14) is identified as a new target gene of miR-150-5p. miR-150-5p markedly inhibits MMP14 expression in hepatoma cells, and miR-150-5p expression is negative correlation with MMP14 expression in vivo. More important, re-expression of MMP14 in hepatoma cells partially reverses the effect of miR-150-5p in inhibiting cell invasion.

Background The Eastern honey bee, Apis cerana Fabricius, is distributed in southern and eastern Asia, from India and China to Korea and Japan and southeast to the Moluccas. This species is also widely kept for honey production besides Apis mellifera. Apis cerana is also a model organism for studying social behavior, caste determination, mating biology, sexual selection, and host-parasite interactions. Few resources are available for molecular research in this species, and a linkage map was never constructed. A linkage map is a prerequisite for quantitative trait loci mapping and for analyzing genome structure. We used the Chinese honey bee, Apis cerana cerana to construct the first linkage map in the Eastern honey bee. Results F2 workers (N = 103) were genotyped for 126,990 single nucleotide polymorphisms (SNPs). After filtering low quality and those not passing the Mendel test, we obtained 3,000 SNPs, 1,535 of these were informative and used to construct a linkage map. The preliminary map contains 19 linkage groups, we then mapped the 19 linkage groups to 16 chromosomes by comparing the markers to the genome of A. mellfiera. The final map contains 16 linkage groups with a total of 1,535 markers. The total genetic distance is 3,942.7 centimorgans (cM) with the largest linkage group (180 loci) measuring 574.5 cM. Average marker interval for all markers across the 16 linkage groups is 2.6 cM. Conclusion We constructed a high density linkage map for A. c. cerana with 1,535 markers. Because the map is based on SNP markers, it will enable easier and faster genotyping assays than randomly amplified polymorphic DNA or microsatellite based maps used in A. mellifera.

Biogenetic silica displays intricate patterns assembling from nano- to microsize level and interesting non-spherical structures differentiating in specific directions. Several model systems have been proposed to explain the formation of biosilica nanostructures. Of them, phase separation based on the physicochemical properties of organic amines was considered to be responsible for the pattern formation of biosilica. In this paper, using tetraethyl orthosilicate (TEOS, Si(OCH2CH3)4) as silica precursor, phospholipid (PL) and dodecylamine (DA) were introduced to initiate phase separation of organic components and influence silica precipitation. Morphology, structure and composition of the mineralized products were characterized using a range of techniques including field emission scanning electron microscopy (FESEM), transmission electron microscope (TEM), X-ray diffraction (XRD), thermogravimetric and differential thermal analysis (TG-DTA), infrared spectra (IR), and nitrogen physisorption. The results demonstrate that the phase separation process of the organic components leads to the formation of asymmetrically non-spherical silica structures, and the aspect ratios of the asymmetrical structures can be well controlled by varying the concentration of PL and DA. On the basis of the time-dependent experiments, a tentative mechanism is also proposed to illustrate the asymmetrical morphogenesis. Therefore, our results imply that in addition to explaining the hierarchical porous nanopatterning of biosilica, the phase separation process may also be responsible for the growth differentiation of siliceous structures in specific directions. Because organic amine (e.g., long-chair polyamines), phospholipids (e.g., silicalemma) and the phase separation process are associated with the biosilicification of diatoms, our results may provide a new insight into the mechanism of biosilicification.

Choroidal neovascularisation (CNV) that occurs as a result of age-related macular degeneration (AMD) causes severe vision loss among elderly patients. The relationship between diabetes and CNV remains controversial. However, oxidative stress plays a critical role in the pathogenesis of both AMD and diabetes. In the present study, we investigated the influence of diabetes on experimentally induced CNV and on the underlying molecular mechanisms of CNV. CNV was induced via photocoagulation in the ocular fundi of mice with streptozotocin-induced diabetes. The effect of diabetes on the severity of CNV was measured. An immunofluorescence technique was used to determine the levels of oxidative DNA damage by anti-8-hydroxy-2-deoxyguanosine (8-OHdG) antibody, the protein expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and vascular endothelial growth factor (VEGF), in mice with CNV. The production of reactive oxygen species (ROS) in retinal pigment epithelial (RPE) cells that had been cultured under high glucose was quantitated using the 2',7'-dichlorofluorescein diacetate (DCFH-DA) method. p-STAT3 expression was examined using Western blot analysis. RT-PCR and ELISA processes were used to detect VEGF expression. Hyperglycaemia exacerbated the development of CNV in mice. Oxidative stress levels and the expression of p-STAT3 and VEGF were highly elevated both in mice and in cultured RPE cells. Treatment with the antioxidant compound N-acetyl-cysteine (NAC) rescued the severity of CNV in diabetic mice. NAC also inhibited the overexpression of p-STAT3 and VEGF in CNV and in RPE cells. The JAK-2/STAT3 pathway inhibitor AG490 blocked VEGF expression but had no effect on the production of ROS in vitro. These results suggest that hyperglycaemia promotes the development of CNV by inducing oxidative stress, which in turn activates STAT3 signalling in RPE cells. Antioxidant supplementation helped attenuate the development of CNV. Thus, our results reveal a potential strategy for the treatment and prevention of diseases involving CNV.

BackgroundIn the honey bee (Apis mellifera), queen and workers have different behavior and reproductive capacity despite possessing the same genome. The primary substance that leads to this differentiation is royal jelly (RJ), which contains a range of proteins, amino acids, vitamins and nucleic acids. MicroRNA (miRNA) has been found to play an important role in regulating the expression of protein-coding genes and cell biology. In this study, we characterized the miRNAs in RJ from two honey bee sister species and determined their possible effect on transcriptome in one species.Methodology/principal findingsWe sequenced the miRNAs in RJ either from A. mellifera (RJM) or A. cerana (RJC). We then determined the global transcriptomes of adult A. mellifera developed from larvae fed either with RJM (mRJM) or RJC (mRJC). Finally we analyzed the target genes of those miRNA that are species specific or differentially expressed in the two honey bee species. We show that there were differences in miRNA between RJM and RJC, and that transcriptomes of adult A. mellifera were affected by the two types of RJ. A high proportion (23.3%) of the affected genes were target genes of differential miRNAs.ConclusionWe show for the first time that there are differences in miRNAs in RJ between A. mellifera and A. cerana. Further, the differences in transcriptomes of bees reared from these two RJs might be related to miRNA differences of the two species. This study provides the first evidence that heterospecific royal jelly can modify gene expression in honey bees through an epigenetic mechanism.

Hyaluronic acid (HA) is a component of the Extra-cellular matrix (ECM), it is closely correlated with tumor cell growth, proliferation, metastasis and angiogenesis, etc. Hyaluronidase (HAase) is a HA-degrading endoglycosidase, levels of HAase are elevated in many cancers. Hyaluronidase-1 (HYAL1) is the major tumor-derived HAase. We previously demonstrated that HYAL1 were overexpression in human breast cancer. Breast cancer cells with higher HAase expression, exhibited significantly higher invasion ability through matrigel than those cells with lower HAase expression, and knockdown of HYAL1 expression in breast cancer cells resulted in decreased cell growth, adhesion, invasion and angiogenesis. Here, to further elucidate the function of HYAL1 in breast cancer, we investigated the consequences of forcing HYAL1 expression in breast cancer cells by transfection of expression plasmid. Compared with control, HYAL1 up-regulated cells showed increased the HAase activity, and reduced the expression of HA in vitro. Meantime, upregulation of HYAL1 promoted the cell growth, migration, invasion and angiogenesis in vitro. Moreover, in nude mice model, forcing HYAL1 expression induced breast cancer cell xenograft tumor growth and angiogenesis. Interestingly, the HA expression was upregulated by forcing HYAL1 expression in vivo. These findings suggested that HYAL1-HA system is correlated with the malignant behavior of breast cancer.

Choroidal neovascularization (CNV) is the common pathological basis of irreversible visual impairment encountered in a variety of chorioretinal diseases; the pathogenesis of its development is complicated and still imperfectly understood. Recent studies indicated that delta-like ligand 4 (Dll4), one of the Notch family ligands might participate in the HIF-1α-VEGF pathway to regulate CNV angiogenesis. But little is known about the influence and potential mechanism of Dll4/Notch signals on CNV angiogenesis. Real-time RT-PCR, Western blotting were used to analyze the expression alteration of Dll4, VEGF and HIF-1α in hypoxic RF/6A cells. Immunofluorescence staining, a laser-induced rat CNV model and intravitreal injection techniques were used to confirm the relationships among these molecules in vitro and in vivo. RPE-RF/6A cell co-culture systems were used to investigate the effects of Dll4/Notch signals on CNV angiogenesis. We found that the Dll4 was involved in hypoxia signaling in CNV angiogenesis. Results from the co-culture system showed that the enhancement of Dll4 expression in RF/6A cells led to the significantly faster proliferation and stronger tube forming ability, but inhibited cells migration and invasion across a monolayer of RPE cells in hypoxic environment, while siRNA-mediated Dll4 silencing caused the opposite effects. Pharmacological disruption of Notch signaling using gamma-secretase inhibitor (GSI) produced similar, but not identical effects, to that caused by the Dll4 siRNA. In addition, the expression of several key molecules involved in the angiogenesis of CNV was altered in RF/6A cells showing constitutively active Dll4 expression. These results suggest that Dll4 play an important role in CNV angiogenesis, which appears to be regulated by HIF-1α and VEGF during the progression of CNV under hypoxic conditions. Targeting Dll4/Notch signaling may facilitate further understanding of the mechanisms that underlie CNV angiogenesis.

Background Young larvae of the honey bee (Apis mellifera) are totipotent; they can become either queens (reproductives) or workers (largely sterile helpers). DNA methylation has been shown to play an important role in this differentiation. In this study, we examine the contributions of diet and cell size to caste differentiation. Methodology/Principal Findings We measured the activity and gene expression of one key enzyme involved in methylation, Dnmt3; the rates of methylation in the gene dynactin p62; as well as morphological characteristics of adult bees developed either from larvae fed with worker jelly or royal jelly; and larvae raised in either queen or worker cells. We show that both diet type and cell size contributed to the queen-worker differentiation, and that the two factors affected different methylation sites inside the same gene dynactin p62. Conclusions/Significance We confirm previous findings that Dnmt3 plays a critical role in honey bee caste differentiation. Further, we show for the first time that cell size also plays a role in influencing larval development when diet is kept the same.