Minocycline,levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease

Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.     

The relationship between anthropometric indexes of adiposity and vascular function in the FATE cohort

Objective:

Numerous indexes of adiposity have been proposed and are currently in use in clinical practice and research. However, the correlation of these indexes with measures of vascular health remain poorly defined. This study investigated which measure of adiposity is most strongly associated with endothelial function.

Design and Methods:

Data from the Firefighters And Their Endothelium (FATE) study was used. The relationships between three measures of vascular function: flow‐mediated dilation (FMD), hyperemic velocity time integral (VTI), and hyperemic shear stress (HSS), and five measures of adiposity: BMI, waist circumference (WC), waist‐to‐hip ratio (WHR), waist‐to‐height ratio (WHtR), and body adiposity index (BAI) were tested. Univariate comparisons were made, and subsequently models adjusted for traditional risk factors were constructed.

Results:

A total of 1,462 male firefighters (mean age 49 ± 9) without cardiovascular disease comprised the study population. No measure of adiposity correlated with FMD; all five measures of adiposity were negatively correlated with VTI and HSS (P values <0.0001), with WHtR most strongly correlated with VTI, and WC most strongly correlated with HSS (both P < 0.05). In models including all five measures of obesity simultaneously, BMI, WC, and WHtR were all predictive of HSS (all P values <0.05), and BMI and WHR were both predictive of VTI (P values <0.05).

Conclusions:

Anthropometric measures of adiposity may help refine estimations of atherosclerotic burden. BMI was most consistently associated with endothelial dysfunction, but measures of adiposity that reflect distribution of mass were additive.     

Fully Automated Enhanced Tumor Compartmentalization: Man vs. Machine Reloaded

ObjectiveComparison of a fully-automated segmentation method that uses compartmental volume information to a semi-automatic user-guided and FDA-approved segmentation technique.MethodsNineteen patients with a recently diagnosed and histologically confirmed glioblastoma (GBM) were included and MR images were acquired with a 1.5 T MR scanner. Manual segmentation for volumetric analyses was performed using the open source software 3D Slicer version 4.2.2.3 (www.slicer.org). Semi-automatic segmentation was done by four independent neurosurgeons and neuroradiologists using the computer-assisted segmentation tool SmartBrush® (referred to as SB), a semi-automatic user-guided and FDA-approved tumor-outlining program that uses contour expansion. Fully automatic segmentations were performed with the Brain Tumor Image Analysis (BraTumIA, referred to as BT) software. We compared manual (ground truth, referred to as GT), computer-assisted (SB) and fully-automated (BT) segmentations with regard to: (1) products of two maximum diameters for 2D measurements, (2) the Dice coefficient, (3) the positive predictive value, (4) the sensitivity and (5) the volume error.ResultsSegmentations by the four expert raters resulted in a mean Dice coefficient between 0.72 and 0.77 using SB. BT achieved a mean Dice coefficient of 0.68. Significant differences were found for intermodal (BT vs. SB) and for intramodal (four SB expert raters) performances. The BT and SB segmentations of the contrast-enhancing volumes achieved a high correlation with the GT. Pearson correlation was 0.8 for BT; however, there were a few discrepancies between raters (BT and SB 1 only). Additional non-enhancing tumor tissue extending the SB volumes was found with BT in 16/19 cases. The clinically motivated sum of products of diameters measure (SPD) revealed neither significant intermodal nor intramodal variations. The analysis time for the four expert raters was faster (1 minute and 47 seconds to 3 minutes and 39 seconds) than with BT (5 minutes).ConclusionBT and SB provide comparable segmentation results in a clinical setting. SB provided similar SPD measures to BT and GT, but differed in the volume analysis in one of the four clinical raters. A major strength of BT may its independence from human interactions, it can thus be employed to handle large datasets and to associate tumor volumes with clinical and/or molecular datasets ("-omics") as well as for clinical analyses of brain tumor compartment volumes as baseline outcome parameters. Due to its multi-compartment segmentation it may provide information about GBM subcompartment compositions that may be subjected to clinical studies to investigate the delineation of the target volumes for adjuvant therapies in the future.     

Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain

Most p53 mutations associated with cancer are located in its DNA binding domain (DBD). Many structures (X‐ray and NMR) of this domain are available in the protein data bank (PDB) and a vast conformational heterogeneity characterizes the various free and complexed states. The major difference between the apo and the holo‐complexed states appears to lie in the L1 loop. In particular, the conformations of this loop appear to depend intimately on the sequence of DNA to which it binds. This conclusion builds upon recent observations that implicate the tetramerization and the C‐terminal domains (respectively TD and Cter) in DNA binding specificity. Detailed PCA analysis of the most recent collection of DBD structures from the PDB have been carried out. In contrast to recommendations that small molecules/drugs stabilize the flexible L1 loop to rescue mutant p53, our study highlights a need to retain the flexibility of the p53 DNA binding surface (DBS). It is the adaptability of this region that enables p53 to engage in the diverse interactions responsible for its functionality. Proteins 2016; 84:1443–1461. © 2016 Wiley Periodicals, Inc.     

Interaction of cobalt(II) and copper(II) hydroxamates with polyriboadenylic acid: An insight into RNA based drug designing

The polyadenylic acid [poly(A)] tail of mRNA plays a noteworthy role in the initiation of the translation, maturation, and stability of mRNA. It also significantly contributes to the production of alternate proteins in eukaryotic cells. Hence, it has recently been recognized as a prospective drug target. Binding affinity of bis(N-p-tolylbenzohydroxamato)Cobalt(II), [N-p-TBHA-Co(II)] (1) and bis(N-p-naphthylbenzohydroxamato)Copper(II), [N-p-NBHA-Cu(II)] (2) complexes with poly(A) have been investigated by biophysical techniques namely, absorption spectroscopy, fluorescence spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, circular dichroism spectroscopy, viscometric measurements and through molecular docking studies. The intrinsic binding constants (K_b) of complexes were determined following the order of N-p-TBHA-Co(II)] > N-p-NBHA-Cu(II), along with hyperchromism and a bathochromic shift for both complexes. The fluorescence quenching method revealed an interaction between poly(A)-N-p-TBHA-Co(II)/poly(A)-N-p-NBHA-Cu(II). The mode of binding was also determined via the fluorescence ferrocyanide quenching method. The increase in the viscosity of poly(A) that occurred from increasing the concentration of the N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) complex was scrutinized. The characteristics of the interaction site of poly(A) with N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) were adenine and phosphate groups, as revealed by DRS-FTIR spectroscopy. Based on these observations, a partial intercalative mode of the binding of poly(A) has been proposed for both complexes. Circular dichroism confirmed the interaction of both the complexes with poly(A). The molecular docking results illustrated that complexes strongly interact with poly(A) via the relative binding energies of the docked structure as ?259.39eV and ?226.30eV for N-p-TBHA-Co(II) and N-p-NBHA-Cu(II) respectively. Moreover, the binding affinity of N-p-TBHA-Co(II) is higher in all aspects than N-p-NBHA-Cu(II) for poly(A).     

Effect of tannery sludge amendments on the activity of soil enzymes and phytoremediation potential of two economically important cultivars of geranium (Pelargonium graveolens)

A field experiment was conducted to observe the effect of TS amendments on soil enzymes and phytoremediation potential of two economically important cultivars of geranium. Different doses of TS were applied in soil to examine threshold limit of HMs where geranium cultivars can be grown successfully in contaminated sites. Treatment variation significantly affected pH, EC, OC, N, P, K and HM content in soil after 50 days of incubation. After harvest, both cultivars were examined to assess the impact of various treatments on their fresh herb, dry matter, essential oil yield and HM accumulation. C/G ratio close to 1 was observed at 50 tha^?1 sludge treatment in both cultivars. Urease and β-glucosidase activities in soil were maximum at 50 tha^?1 whereas dehydrogenase and phosphatase activities were maximum at 100 tha^?1 in both cultivars. β-glucosidase, acid and alkaline phosphatase, urease and dehydrogenase activities were relatively high after 85 days over 45 days in both cultivars. Maximum metal uptake was found in roots of cv. Bourbon followed by leaves. Geranium was observed to be a good candidate for phytoremediation as it mitigates metal toxicity by root absorption and cv. Bourbon is better candidate for the same.     

A Simple Multi-band Metamaterial Absorber with Combined Polarization Sensitive and Polarization Insensitive Characteristics for Terahertz Applications

This paper presents a simple multi-band metamaterial absorber for terahertz applications. The unit cell of the proposed structure consists of a single square ring having gaps at the centers on three of its sides. The proposed absorber produces three absorption bands for all polarizations and hence the design can be considered as insensitive to polarization variation. It provides an average absorption of 96.92% for the TE polarization with a peak absorption of 99.44% at 3.87 THz and for the TM polarization, it provides an average absorption of 98.4% with a peak absorption of 99.86% at 3.87 THz. An additional absorption peak is observed for the TE polarization at 1.055 THz that gradually diminishes with the increase in polarization angle and completely vanishes for the TM polarization. Thus, the structure displays a hybrid polarization response with polarization insensitivity in three bands and polarization sensitivity in one band. Parametric analysis has been carried out validating the optimal selection of the design parameters. The simplicity of the design and its combined polarization sensitive and polarization insensitive absorption characteristics can find tremendous applications in the field of terahertz imaging and sensing.