A Study Assessing the Association of Glycated Hemoglobin A1C (HbA1C) Associated Variants with HbA1C,Chronic Kidney Disease and Diabetic Retinopathy in Populations of Asian Ancestry

Glycated hemoglobin A_1C (HbA_1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA_1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA_1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA_1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA_1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA_1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.     

Therapeutic Effect of Hydrogen Sulfide-Releasing L-Dopa Derivative ACS84 on 6-OHDA-Induced Parkinson’s Disease Rat Model

Parkinson’s disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson’s disease.     

A Conserved Genetic Pathway Determines Inflorescence Architecture in Arabidopsis and Rice

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Highlights? SOC1, SVP, AGL24, and SEP4 directly repress TFL1 in emerging floral meristems ? SOC1, SVP, AGL24, and SEP4 interact with AP1 to repress TFL1 ? Repression of TFL1 is associated with a conformational change in gene looping ? Function of SOC1, SVP, AGL24, and SEP4 is conserved in Arabidopsis and rice     

Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study

Background

The aim of this study was to verify the benefits and limitations of repeated bedside echocardiographic examinations in children during mechanical ventilation. For the purposes of this study, we selected the data of over a time period from 2006 to 2010.

Methods

A total of 235 children, average age 3.21 (SD 1.32) years were included into the study and divided into etiopathogenic groups. High-risk groups comprised: Acute lung injury and acute respiratory distress syndrome (ALI/ARDS), return of spontaneous circulation after cardiopulmonary resuscitation (ROSC), bronchopulmonary dysplasia (BPD), cardiomyopathy (CMP) and cardiopulmonary disease (CPD). Transthoracic echocardiography was carried out during mechanical ventilation. The following data were collated for statistical evaluation: right and left ventricle myocardial performance indices (RV MPI; LV MPI), left ventricle shortening fraction (SF), cardiac output (CO), and the mitral valve ratio of peak velocity of early wave (E) to the peak velocity of active wave (A) as E/A ratio. The data was processed after a period of recovery, i.e. one hour after the introduction of invasive lines (time-1) and after 72 hours of comprehensive treatment (time-2). The overall development of parameters over time was compared within groups and between groups using the distribution-free Wilcoxons and two-way ANOVA tests.

Results

A total of 870 echocardiographic examinations were performed. At time-1 higher average values of RV MPI (0.34, SD 0.01 vs. 0.21, SD 0.01; p < 0.001) were found in all groups compared with reference values. Left ventricular load in the high-risk groups was expressed by a higher LV MPI (0.39, SD 0.13 vs. 0.29, SD 0.02; p < 0.01) and lower E/A ratio (0.95, SD 0.36 vs. 1.36, SD 0.64; p < 0.001), SF (0.37, SD 0.11 vs. 0.47, SD 0.02; p < 0.01) and CO (1.95, SD 0.37 vs. 2.94, SD 1.03; p < 0.01). At time-2 RV MPI were lower (0.25, SD 0.02 vs. 0.34, SD 0.01; p < 0.001), but remained higher compared with reference values (0.25, SD 0.02 vs. 0.21, SD 0.01; p < 0.05). Other parameters in high-risk groups were improved, but remained insignificantly different compared with reference values.

Conclusion

Echocardiography complements standard monitoring of valuable information regarding cardiac load in real time. Chest excursion during mechanical ventilation does not reduce the quality of the acquired data.     

PI3 Kinase inhibition on TRAIL-induced apoptosis correlates with androgen-sensitivity and p21 expression in prostate cancer cells

TNF-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many types of cancer cells. TRAIL is considered a therapeutic target, therefore, it was of interest to examine molecular mechanisms that may modulate sensitivity to TRAIL signaling in prostate cancer cells. LNCaP cells were found to be relatively resistant to TRAIL induced cell death while PC3 cells were sensitive. PI3-kinase (PI3 K) inhibitors were able to render LNCaP cells sensitive to TRAIL but conferred resistance to PC3 cells. PI3 K inhibitors were associated with an increase in p21^{waf1, cip1} expression in PC3 cells where as p21 decreases in LNCaP cells suggesting that p21 may impart TRAIL resistance. Since androgen receptor (AR) signaling can be modulated by AKT, and p21 is an AR responsive gene, the impact of PI3 K inhibition on TRAIL sensitivity was evaluated in AR transfected PC3 cells (PC3AR). The expression of AR was significantly downregulated by PI3 K inhibition in LNCaP cells, which have an intact AR signaling axis. PC3AR cells expressed higher levels of p21 protein and were relatively resistant to TRAIL compared to control cells. Finally, using adenoviral p21 gene transfer we directly demonstrated that p21 can confer resistance to TRAIL-induced cell death. These results suggest that TRAIL resistance is not regulated simply by a PI3 K/AKT survival pathway associated with inactivating PTEN mutations but may also be modulated by downstream AR responsive targets such as p21. These findings may have significant clinical implications for the utility of TRAIL in the management of prostate cancer.     

Combining high-energy C-trap dissociation and electron transfer dissociation for protein O-GlcNAc modification site assignment

Mass spectrometry-based studies of proteins that are post-translationally modified by O-linked β-N-acetylglucosamine (O-GlcNAc) are challenged in effectively identifying the sites of modification while simultaneously sequencing the peptides. Here we tested the hypothesis that a combination of high-energy C-trap dissociation (HCD) and electron transfer dissociation (ETD) could specifically target the O-GlcNAc modified peptides and elucidate the amino acid sequence while preserving the attached GlcNAc residue for accurate site assignment. By taking advantage of the recently characterized O-GlcNAc-specific IgG monoclonal antibodies and the combination of HCD and ETD fragmentation techniques, O-GlcNAc modified proteins were enriched from HEK293T cells and subsequently characterized using the LTQ Orbitrap Velos ETD (Thermo Fisher Scientific) mass spectrometer. In our data set, 83 sites of O-GlcNAc modification are reported with high confidence confirming that the HCD/ETD combined approach is amenable to the detection and site assignment of O-GlcNAc modified peptides. Realizing HCD triggered ETD fragmentation on a linear ion trap/Orbitrap platform for more in-depth analysis and application of this technique to other post-translationally modified proteins are currently underway. Furthermore, this report illustrates that the O-GlcNAc transferase appears to demonstrate promiscuity with regards to the hydroxyl-containing amino acid modified in short stretches of primary sequence of the glycosylated polypeptides.     

Partially glycosylated dendrimers block MD-2 and prevent TLR4-MD-2-LPS complex mediated cytokine responses

The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4'phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases.     

Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia

Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.