MiR-1303 Regulates Mycobacteria Induced Autophagy by Targeting Atg2B

MicroRNAs are emerging post-transcriptional regulators of gene expressions in both innate immunity and adaptive immunity. In mycobacteria infection, autophagy plays an important role in innate defense mechanism and is tightly regulated by the autophagy-related proteins. Here, we show that Atg2B is involved in the regulation of mycobacteria-induced autophagy. MiR-1303, which function is not defined yet, is found to negatively regulate mycobacteria-induced Atg2B protein production, ultimately down-regulate mycobacteria-induced autophagy. MiR-1303 production is shown to be upregulated during BCG infection and its production is regulated by PI3K and NFκB. It is also demonstrated that miR-1303 targets putative target sites on Atg2B and possibly represses its translation.published_or_final_versio

The role of c-Myc in phagocytosis of mycobacteria in human macrophages

Poster Presentation (Doctor’s Session)This journal issue contain proceedings of the CongressMycobacterium tuberculosis is an intracellular pathogen and the causative agent of the disease tuberculosis. Macrophages are the major immunocytes to initiate host immunity against mycobacteria. Among the multiple strategies employ by macrophages to defence against mycobacteria, phagocytosis is the first step. Throughphagocytosis, macrophages could not only clear the pathogens from infection sites, but also present antigens derived from the engulfed bacteria to lymphoid cells. c-Myc is a transcription factor that regulates a variety of target genes. It can form a complex with Max and bind to the enhancer box sequences of the promoter to mediate the transcription. Recently, our group revealed that c-Myc has a potential role in regulating the antimicrobial responses in macrophages. Here, we further revealed that c-Myc may play a positive role in phagocytosis and contribute to host defense to mycobacteria. Pretreatment of c-Myc inhibitor, 10058-F4, could significantly reduce the amount of mycobacteria internalised by macrophages. The acidification of phagolysosome in mycobacteria infected macrophages was also inhibited by 10058-F4. Further investigation showed that macrophages phagocytose mycobacteria in a PI3K/Akt independent pathway. And the action of c-Myc inhibitor does not affect the expression levels of Rho family GTPases. However, we found that 10058-F4 could significantly inhibit phorsphorylation of ERK1/2 kinase, which has been indicated to play a role in FcR mediated phagocytosis in macrophage. In conclusion, c-Myc may play a role in phagocytosis of mycobacteria through regulating phorsphorylation of ERK1/2.published_or_final_versio

The role of oncogene in mycobacteria-induced antophagy in human macrophages

Poster PresentationMacrophages are the major immunocytes to initiate both innate and adaptive immune responses against Mycobacterium tuberculosis (Mtb), a causative agent of tuberculosis. Upon mycoabcteria infection, macrophages could eliminate the intracellular bacteria through different cell death pathways, including apoptosis and autophagy. c-Myc is a transcription factor that regulates a variety of target genes and control different cellular functions such as proliferation and immune resposnse. Recently, our group revealed that c-Myc has a potential role in regulating the antimicrobial responses in macrophages. Here we use BCG, a live attenuated strain of Mycobacterium bovis, which is similar to Mtb in antigenic composition, as a model to study the role of c-Myc in regulating mycobacteria-induced autophagy. We first investigated the role of c-Myc in BCG-induced LC3BII levels. Knocking down c-Myc by siRNA could decrease BCG-induced LC3BII levels. We found that BCG-induced autophagy is dependent on JNK and p38 and independent on PI3K or ERK pathways. And knocking down of c-Myc could significantly inhibit phosphorylation of p38. In conclusion, c-Myc may play a positive role in mycobacteria-induced autophagy in human macrophages.published_or_final_versio

Investigating the role of interleukin-17A on cytokines production by macrophages in response to bacterial infections

Poster PresentationInterleukin-17A (IL-17A) has been shown to associate with a variety of infection diseases. In this study, we investigate whether IL-17A affects cytokines production of human peripheral blood-derived macrophages during Mycobacteriun bovis BCG or Klebsiella pneumoniae infection. We observed that IL-17A-treated macrophages exhibited suppressed productions of TNF-α and IL-6 in response to BCG infection. The reduction of cytokines production was not associated with cell death. On the other hand, IL-17A promoted TNF-α and IL-6 production by macrophages during K. pneumoniae infection. Furthermore, IL-17A did not affect TNF-α production induced by LPS and Pam3 Cys, which are TLR4 and TLR2 agonists, respectively. The data suggest that the differential regulation of cytokines production by IL-17A requires whole bacterium infection.published_or_final_versio

Dynamic self-assembly of DNA minor groove-binding ligand DB921 into nanotubes triggered by an alkali halide.

We describe a novel self-assembling supramolecular nanotube system formed by a heterocyclic cationic molecule which was originally designed for its potential as an antiparasitic and DNA sequence recognition agent. Our structural characterisation work indicates that the nanotubes form via a hierarchical assembly mechanism that can be triggered and tuned by well-defined concentrations of simple alkali halide salts in water. The nanotubes assembled in NaCl have inner and outer diameters of ca. 22 nm and 26 nm respectively, with lengths that reach into several microns. Our results suggest the tubes consist of DB921 molecules stacked along the direction of the nanotube long axis. The tubes are stabilised by face-to-face π-π stacking and ionic interactions between the charged amidinium groups of the ligand and the negative halide ions. The assembly process of the nanotubes was followed using small-angle X-ray and neutron scattering, transmission electron microscopy and ultraviolet/visible spectroscopy. Our data demonstrate that assembly occurs through the formation of intermediate ribbon-like structures that in turn form helices that tighten and compact to form the final stable filament. This assembly process was tested using different alkali-metal salts, showing a strong preference for chloride or bromide anions and with little dependency on the type of cation. Our data further demonstrates the existence of a critical anion concentration above which the rate of self-assembly is greatly enhanced

Effect of hypoxia-inducible factor-1α on transcription of survivin in non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Survivin is a structurally and functionally unique member of the inhibitor of apoptosis protein (IAP) family. It plays an important role, not only in regulating mitosis but also in inhibiting apoptosis. The current literature contains few reports on the transcriptional regulation of survivin expression in lung cancer.</p> <p>Methods</p> <p>In this study, we investigated the effect of hypoxia-inducible factor-1α (HIF-1α) on the transcriptional activity of the survivin promoter in non-small cell lung cancer (NSCLC). Immunohistochemical staining was used to detect the expression of survivin and HIF-1α in the lung tissue of 120 patients with non-small cell lung cancer (NSCLC) and 40 patients with benign pulmonary disease. We also performed experiments with the lung adenocarcinoma cell line A549 cells, which were cultured under hypoxic conditions. The expression of survivin and HIF-1α was detected by real-time RT-PCR and Western blotting. In the survivin promoter the putative binding-site for HIF-1α, is -19 bp~-16 bp upstream of TSS. We performed site-directed mutagenesis of this binding site, and used luciferase reporter plasmids to determine the relative activity of the survivin promoter in A549 cells. We also studied the effect of HIF-1α on the expression of survivin by dsRNA targeting of HIF-1α mRNA.</p> <p>Results</p> <p>HIF-1α (58.33%) and survivin (81.60%) were both over-expressed in NSCLC and their expressions correlated with one another. They were also expressed in A549 cells under normal and hypoxic conditions, with a significant increase under hypoxic conditions. Site directed mutagenesis of the putative binding site for HIF-1α in the survivin promoter significantly decreased the activity of the survivin promoter in A549 cells. Inhibition of HIF-1α by RNAi decreased the expression of survivin in A549 cell lines.</p> <p>Conclusion</p> <p>Our results indicate that the binding of HIF-1α to the survivin promoter increases transcription of the survivin gene. Thus, HIF-1α is an important transcriptional regulator of survivin expression</p

Comparison of Mortality Outcomes in Acute Myocardial Infarction Patients With or Without Standard Modifiable Cardiovascular Risk Factors

Background: Acute myocardial infarction (AMI) cases have decreased in part due to the advent of targeted therapies for standard modifiable cardiovascular disease risk factors (SMuRF). Recent studies have reported that ST-elevation myocardial infarction (STEMI) patients without SMuRF (termed "SMuRF-less") may be increasing in prevalence and have worse outcomes than "SMuRF-positive" patients. As these studies have been limited to STEMI and comprised mainly Caucasian cohorts, we investigated the changes in the prevalence and mortality of both SMuRF-less STEMI and non-STEMI (NSTEMI) patients in a multiethnic Asian population. Methods: We evaluated 23,922 STEMI and 62,631 NSTEMI patients from a national multiethnic registry. Short-term cardiovascular and all-cause mortalities in SMuRF-less patients were compared to SMuRF-positive patients. Results: The proportions of SMuRF-less STEMI but not of NSTEMI have increased over the years. In hospitals, all-cause and cardiovascular mortality and 1-year cardiovascular mortality were significantly higher in SMuRF-less STEMI after adjustment for age, creatinine, and hemoglobin. However, this difference did not remain after adjusting for anterior infarction, cardiopulmonary resuscitation (CPR), and Killip class. There were no differences in mortality in SMuRF-less NSTEMI. In contrast to Chinese and Malay patients, SMuRF-less patients of South Asian descent had a two-fold higher risk of in-hospital all-cause mortality even after adjusting for features of increased disease severity. Conclusion: SMuRF-less patients had an increased risk of mortality with STEMI, suggesting that there may be unidentified nonstandard risk factors predisposing SMuRF-less patients to a worse prognosis. This group of patients may benefit from more intensive secondary prevention strategies to improve clinical outcomes

The prognosis of allocentric and egocentric neglect : evidence from clinical scans

We contrasted the neuroanatomical substrates of sub-acute and chronic visuospatial deficits associated with different aspects of unilateral neglect using computed tomography scans acquired as part of routine clinical diagnosis. Voxel-wise statistical analyses were conducted on a group of 160 stroke patients scanned at a sub-acute stage. Lesion-deficit relationships were assessed across the whole brain, separately for grey and white matter. We assessed lesions that were associated with behavioural performance (i) at a sub-acute stage (within 3 months of the stroke) and (ii) at a chronic stage (after 9 months post stroke). Allocentric and egocentric neglect symptoms at the sub-acute stage were associated with lesions to dissociated regions within the frontal lobe, amongst other regions. However the frontal lesions were not associated with neglect at the chronic stage. On the other hand, lesions in the angular gyrus were associated with persistent allocentric neglect. In contrast, lesions within the superior temporal gyrus extending into the supramarginal gyrus, as well as lesions within the basal ganglia and insula, were associated with persistent egocentric neglect. Damage within the temporo-parietal junction was associated with both types of neglect at the sub-acute stage and 9 months later. Furthermore, white matter disconnections resulting from damage along the superior longitudinal fasciculus were associated with both types of neglect and critically related to both sub-acute and chronic deficits. Finally, there was a significant difference in the lesion volume between patients who recovered from neglect and patients with chronic deficits. The findings presented provide evidence that (i) the lesion location and lesion size can be used to successfully predict the outcome of neglect based on clinical CT scans, (ii) lesion location alone can serve as a critical predictor for persistent neglect symptoms, (iii) wide spread lesions are associated with neglect symptoms at the sub-acute stage but only some of these are critical for predicting whether neglect will become a chronic disorder and (iv) the severity of behavioural symptoms can be a useful predictor of recovery in the absence of neuroimaging findings on clinical scans. We discuss the implications for understanding the symptoms of the neglect syndrome, the recovery of function and the use of clinical scans to predict outcome

Graphene plasmonics

Two rich and vibrant fields of investigation, graphene physics and plasmonics, strongly overlap. Not only does graphene possess intrinsic plasmons that are tunable and adjustable, but a combination of graphene with noble-metal nanostructures promises a variety of exciting applications for conventional plasmonics. The versatility of graphene means that graphene-based plasmonics may enable the manufacture of novel optical devices working in different frequency ranges, from terahertz to the visible, with extremely high speed, low driving voltage, low power consumption and compact sizes. Here we review the field emerging at the intersection of graphene physics and plasmonics.Comment: Review article; 12 pages, 6 figures, 99 references (final version available only at publisher's web site